Genetic DiseaseBeginNGSNCT06306521
An Adaptive Clinical Trial of BeginNGS Newborn Screening for Hundreds of Genetic Diseases by Genome Sequencing
A study testing BeginNGS Test in people with Genetic Disease, run by Rady Pediatric Genomics & Systems Medicine Institute at 1 site in United States.
Trial summary
The goal of this clinical trial is to test a new method for newborn screening using whole genome sequencing, called BeginNGS. Parents will be approached to provide informed consent to enroll their newborns in prenatal, postnatal, and outpatient settings. Read more about this study
- Who is it for?
- Ages 1 day to 28 daysHealthy volunteers can take part
- Conditions the study is for
- Genetic Disease
- What is being tested?
- BeginNGS Test
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10,000 participants
- Where
- 1 siteUnited States
- Study dates
- 29 Feb 2024to Feb 2029
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 day to 28 days
- All sexes
- Healthy volunteers accepted
- Child
Who may be able to join
- Neonates (<28 days old) at enrollment sites.
- Parents must have identified a primary care provider (or group).
Who cannot join
- Neonates whose mother is less than 18 years of age.
- Neonates who are wards of the state.
- Neonates whose parent/legal guardian is unable to provide consent.
- Parents with a home address outside the US or jurisdiction of the enrollment sites.
- Neonates or fetuses who are ill and in whom enrollment or sampling is anticipated to interfere with healthcare provision at delivery. For example, fetuses or neonates who are likely to require transfer to a higher level of care, such as to a Level IV NICU upon delivery.
- Neonates who are under consideration for a rapid diagnostic genome sequence or other diagnostic genetic testing.
- Neonates who are not expected to survive the neonatal period.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Rady Children's Hospital San Diego
San Diego, California, 92123
Lauren Olsen, MSN, 858-576-1700 ext. 228456, lolsen1@rchsd.org
About this study
The goal of this clinical trial is to test a new method for newborn screening using whole genome sequencing, called BeginNGS. Parents will be approached to provide informed consent to enroll their newborns in prenatal, postnatal, and outpatient settings. The main questions this study aims to answer are:
What is the utility of BeginNGS as compared to state newborn screening? What is the acceptability and feasibility of BeginNGS as compared to state newborn screening? What is the cost effectiveness of BeginNGS as compared to state newborn screening?
Enrolled newborns will have a blood sample taken and will receive the BeginNGS test. Newborns will have also had the state newborn screening test.
Read the detailed description
Each year 98% of US newborns receive screening (NBS) of dried blood spots (DBS) for at least 35 Recommended Uniform Screening Panel (RUSP) genetic disorders for diagnosis and treatment at/before onset of symptoms. About 6,600 true positive infants are identified per year. NBS is well-accepted and has proven clinical utility. Between 2010 and 2022, however, while many new therapeutic interventions for childhood genetic diseases showed clinical utility and/or were approved by the Food and Drug Administration (FDA), only 6 disorders were added to the RUSP. As a result, ~700 childhood genetic diseases have effective treatments but are not yet screened by NBS, and affected children experience delayed diagnosis and treatment, and poor outcomes. To solve this problem the investigators are developing BeginNGS - NBS by genome sequencing (GS) of DBS for, ultimately, ~700 severe, childhood genetic diseases with effective therapeutic interventions. BeginNGS is adaptive: genetic disorders are added (or removed) as evidence emerges that early treatment improves (or does not improve) outcomes. BeginNGS version 1 (v1, 388 genetic disorders) had good sensitivity (88.8%) and false positive rate (0.27%) in a retrospective study of 458,000 subjects. An exploratory prospective clinical trial comparing BeginNGS v2 (with 409 disorders) and rapid diagnostic genome sequencing (RDGS) identified reportable findings in 24 (34%) of 71 acutely ill newborns who were not suspected of having a genetic disease. Only 2 of those disorders were detected by standard NBS. The investigators propose a single group, multicenter, adaptive clinical trial to compare utility, acceptability, feasibility, and cost effectiveness of BeginNGS (experimental intervention) with standard NBS (control) in a minimum of 10,000 neonates (aged <28 days, maximum of 100,000). The primary objective of the trial is to generate evidence to support broad implementation of BeginNGS. An adaptive design was chosen rather than a traditional, fixed design to allow accumulating results to make the trial more efficient, informative, and ethical by addition or removal of BeginNGS disorders and genetic variants, population enrichment (for minority racial, ethnic, and ancestral groups), and sample size re-estimation. Adaptive design will also facilitate meta-analysis with other clinical trials of NBS-by-GS, providing greater power to test utility in ultra-rare genetic diseases. NBS-by-GS has the potential to transform the way childhood genetic diseases are diagnosed and treatments started. Preliminary data suggest that national adoption of BeginNGS in all births has the potential to improve outcomes of >50,000 US children per year.
- Conditions
- Genetic Disease
- Being tested
- BeginNGS Test
- Keywords
- newborn screening
- Medical subject headings
- Genetic Diseases, Inborn
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BeginNGS TestGenetic
Genomic sequencing that screens for over 400 genetic diseases.
| Study group | Role | What they receive |
|---|---|---|
| Enrollees | Experimental | Enrolled infants will receive the BeginNGS test in addition to the state newborn screen. Receives: Genetic: BeginNGS Test |
What is being measured
The primary outcome is the main question the study is designed to answer.
Comparison of the clinical utility of BeginNGS and standard of care (state NBS), defined by the proportion of enrollees likely to benefit (likely to have an improved outcome) from an indicated therapeutic intervention
The proportion of enrollees likely to benefit (likely to have an improved outcome) from an indicated therapeutic intervention (as per an electronic clinical management system, Genome-to-Treatment, GTRx)
Measured: 5 years
Secondary outcomes (29)
Utility secondary outcome 1
The proportion of BeginNGS and state NBS of DBS that are positive (Positive rate)
Measured: 5 years
Utility secondary outcome 2
The proportion of BeginNGS and state NBS of DBS positive results that are confirmed (true positive rate and positive predictive value)
Measured: 5 years
Utility secondary outcome 3
The proportion of BeginNGS and state NBS of DBS that are true positive and diagnosed during infancy.
Measured: 5 years
Utility secondary outcome 4
The proportion of BeginNGS and state NBS of DBS that are true positive and diagnosed at study end.
Measured: 5 years
Utility secondary outcome 5
The proportion of BeginNGS and state NBS of DBS that are positive and in whom an indicated therapeutic intervention was commenced by study end.
Measured: 5 years
Utility secondary outcome 6
The proportion of BeginNGS and state NBS of DBS that are positive and in whom a disease outcome changed due to a therapeutic intervention by study end.
Measured: 5 years
Utility secondary outcome 7
Subgroup analysis of clinical utility (as defined by the primary outcome measure) by race (black, white, Asian), ethnicity (Hispanic, non-Hispanic), genetic ancestry, and disorder group
Measured: 5 years
Utility secondary outcome 8
Subgroup analysis of positive rate (secondary utility outcome measure 1) by race, ethnicity, genetic ancestry, and disorder group.
Measured: 5 years
Utility secondary outcome 9
Subgroup analysis of true positive rate (secondary utility outcome measure 2) by race, ethnicity, genetic ancestry, and disorder group.
Measured: 5 years
Utility secondary outcome 10
Subgroup analysis of the proportion of BeginNGS and state NBS of DBS that are true positive and diagnosed during infancy in infancy by race, ethnicity, genetic ancestry, and disorder group.
Measured: 5 years
Acceptability outcome 1
Proportion of parents approached who agree to enroll their newborn (Figure 1c①). This is a "key outcome" (as defined by CONSORT PRO31).
Measured: 5 years
Acceptability outcome 2
Physician and parental questionnaires (Figure 1c⑤) regarding perceptions of benefits and harms of BeginNGS by parents and primary care pediatricians.
Measured: 5 years
Acceptability outcome 3
Subgroup analysis of enrollment rate (proportion of parents approached who agree to enroll their newborn; Figure 1c①) by race, ethnicity, genetic ancestry, and enrollment method.
Measured: 5 years
Acceptability outcome 4
Subgroup analysis of parental questionnaires (regarding perceptions of benefits and harms of BeginNGS) by race, ethnicity, and genetic ancestry.
Measured: 5 years
Feasibility (ability of the study to be undertaken as designed) outcome 1
Time to return of a result for BeginNGS and state NBS.
Measured: 5 years
Feasibility (ability of the study to be undertaken as designed) outcome 2
Time to return of a confirmed true positive result of BeginNGS and state NBS.
Measured: 5 years
Feasibility (ability of the study to be undertaken as designed) outcome 3
Proportion of enrollees with positive results who undergo confirmatory testing by BeginNGS and state NBS.
Measured: 5 years
Feasibility (ability of the study to be undertaken as designed) outcome 4
Time to diagnosis (time until a clinical feature of the disorder is identified) for BeginNGS and state NBS.
Measured: 5 years
Feasibility (ability of the study to be undertaken as designed) outcome 5
Proportion of enrollees lost to follow up at one year of age.
Measured: 5 years
Cost effectiveness outcome 1
Average cost effectiveness ratio (ACER, average cost to prevent one infant death or adverse event).
Measured: 5 years
Cost effectiveness outcome 2
Incremental cost effectiveness ratio (ICER, average change in cost associated with prevention of one infant death or adverse event).
Measured: 5 years
Cost effectiveness outcome 3
Subgroup analysis of Average Cost Effectiveness Ratio (ACER, average cost to prevent one infant death or adverse event) by disorder group (for example metabolic disorders, immunodeficiency disorders, seizure disorders, endocrine disorders, vitamin and cofactor deficiency disorders, hematologic disorders, muscle disorders).
Measured: 5 years
Cost effectiveness outcome 4
Subgroup analysis of Incremental cost effectiveness ratio (ICER, average change in cost associated with prevention of one infant death or adverse event) by disorder group (for example metabolic disorders, immunodeficiency disorders, seizure disorders, endocrine disorders, vitamin and cofactor deficiency disorders, hematologic disorders, muscle disorders).
Measured: 5 years
Accuracy outcome 1
True positive rate (true positive/true positive+false negative, recall, sensitivity) of BeginNGS by comparison with state NBS of DBS (all enrollees).
Measured: 5 years
Accuracy outcome 2
True positive rate of BeginNGS by comparison with other genetic tests (in infants who subsequently receive diagnostic testing for a suspected genetic disease).
Measured: 5 years
Utility secondary outcome 11
Number needed to screen to prevent one infant death or adverse event.
Measured: 5 years
Feasibility outcome 6
Incidence of variants and haplotypes associated with individual genetic diseases in newborns.
Measured: 5 years
Feasibility outcome 7
Categorical determination of genetic pattern of inheritance (for example dominant, recessive) of individual genetic diseases in newborns (where this has not been unequivocally established).
Measured: 5 years
Utility secondary outcome 12
Subgroup categorical analysis of efficacy of individual therapeutic interventions in infants.
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Mar 2024
- Study start29 Feb 2024
- Primary completionFeb 2029 (estimated)
- Study completionFeb 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Genetic DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Screening
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10,000 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Rady Pediatric Genomics & Systems Medicine Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Stephen F. Kingsmore, Rady Pediatric Genomics & Systems Medicine Institute
- Investigators
- Stephen Kingsmore, MD DSc, Principal investigator, Rady Children's Institute for Genomic MedicineRebecca Reimers, MD MPH, Principal investigator, Rady Children's Institute for Genomic Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06306521
- Sponsor's protocol ID
- 20235517
- Acronym
- BeginNGS
- Status last verified
- Mar 2024
- First submitted
- 22 Feb 2024
- Last updated
- 12 Mar 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Reimers R, Bailey M, Brown C, Chan K, Defay T, Finkel T, Kahn S, Protopsaltis L, Stoddard L, Talati AJ, Wigby K, Akil ASA, Wright M, Kingsmore SF; BeginNGS Consortium. Clinical utility and cost-effectiveness of BeginNGS newborn screening by genome sequencing and standard newborn screening for severe childhood genetic diseases: an adaptive, international and comparative clinical trial. BMJ Open. 2025 Nov 13;15(11):e098609. doi: 10.1136/bmjopen-2024-098609.
PubMed 41238356
Study at a glance
From the registry record, last updated by the sponsor on 12 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Adaptive Clinical Trial of BeginNGS Newborn Screening for Hundreds of Genetic Diseases by Genome Sequencing
- ClinicalTrials.gov ID
- NCT06306521
- Acronym / sponsor ID
- BeginNGS / 20235517
- Conditions
- Genetic Disease
- Keywords
- newborn screening
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 10,000 participants (estimated)
- Lead sponsor
- Rady Pediatric Genomics & Systems Medicine InstituteUniversity, hospital or other
- Study start
- 29 Feb 2024 (actual)
- Primary completion
- Feb 2029 (estimated)
- Study completion
- Feb 2029 (estimated)
- First posted
- 12 Mar 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this clinical trial is to test a new method for newborn screening using whole genome sequencing, called BeginNGS. Parents will be approached to provide informed consent to enroll their newborns in prenatal, postnatal, and outpatient settings. The main questions this study aims to answer are:
What is the utility of BeginNGS as compared to state newborn screening? What is the acceptability and feasibility of BeginNGS as compared to state newborn screening? What is the cost effectiveness of BeginNGS as compared to state newborn screening?
Enrolled newborns will have a blood sample taken and will receive the BeginNGS test. Newborns will have also had the state newborn screening test.
Detailed description
Each year 98% of US newborns receive screening (NBS) of dried blood spots (DBS) for at least 35 Recommended Uniform Screening Panel (RUSP) genetic disorders for diagnosis and treatment at/before onset of symptoms. About 6,600 true positive infants are identified per year. NBS is well-accepted and has proven clinical utility. Between 2010 and 2022, however, while many new therapeutic interventions for childhood genetic diseases showed clinical utility and/or were approved by the Food and Drug Administration (FDA), only 6 disorders were added to the RUSP. As a result, ~700 childhood genetic diseases have effective treatments but are not yet screened by NBS, and affected children experience delayed diagnosis and treatment, and poor outcomes. To solve this problem the investigators are developing BeginNGS - NBS by genome sequencing (GS) of DBS for, ultimately, ~700 severe, childhood genetic diseases with effective therapeutic interventions. BeginNGS is adaptive: genetic disorders are added (or removed) as evidence emerges that early treatment improves (or does not improve) outcomes. BeginNGS version 1 (v1, 388 genetic disorders) had good sensitivity (88.8%) and false positive rate (0.27%) in a retrospective study of 458,000 subjects. An exploratory prospective clinical trial comparing BeginNGS v2 (with 409 disorders) and rapid diagnostic genome sequencing (RDGS) identified reportable findings in 24 (34%) of 71 acutely ill newborns who were not suspected of having a genetic disease. Only 2 of those disorders were detected by standard NBS. The investigators propose a single group, multicenter, adaptive clinical trial to compare utility, acceptability, feasibility, and cost effectiveness of BeginNGS (experimental intervention) with standard NBS (control) in a minimum of 10,000 neonates (aged <28 days, maximum of 100,000). The primary objective of the trial is to generate evidence to support broad implementation of BeginNGS. An adaptive design was chosen rather than a traditional, fixed design to allow accumulating results to make the trial more efficient, informative, and ethical by addition or removal of BeginNGS disorders and genetic variants, population enrichment (for minority racial, ethnic, and ancestral groups), and sample size re-estimation. Adaptive design will also facilitate meta-analysis with other clinical trials of NBS-by-GS, providing greater power to test utility in ultra-rare genetic diseases. NBS-by-GS has the potential to transform the way childhood genetic diseases are diagnosed and treatments started. Preliminary data suggest that national adoption of BeginNGS in all births has the potential to improve outcomes of >50,000 US children per year.
Study design
- Primary purpose
- Screening
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Enrollees | Experimental | Genetic: BeginNGS TestEnrolled infants will receive the BeginNGS test in addition to the state newborn screen. |
Who may qualify
- Ages
- 1 day to 28 days
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child
Key inclusion criteria (2 listed)
- Neonates (<28 days old) at enrollment sites.
- Parents must have identified a primary care provider (or group).
Key exclusion criteria (7 listed)
- Neonates whose mother is less than 18 years of age.
- Neonates who are wards of the state.
- Neonates whose parent/legal guardian is unable to provide consent.
- Parents with a home address outside the US or jurisdiction of the enrollment sites.
- Neonates or fetuses who are ill and in whom enrollment or sampling is anticipated to interfere with healthcare provision at delivery. For example, fetuses or neonates who are likely to require transfer to a higher level of care, such as to a Level IV NICU upon delivery.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BeginNGS TestGenomic sequencing that screens for over 400 genetic diseases. | Genetic | Enrollees |
Primary outcome
Comparison of the clinical utility of BeginNGS and standard of care (state NBS), defined by the proportion of enrollees likely to benefit (likely to have an improved outcome) from an indicated therapeutic intervention
Time frame: 5 years
The proportion of enrollees likely to benefit (likely to have an improved outcome) from an indicated therapeutic intervention (as per an electronic clinical management system, Genome-to-Treatment, GTRx)
29 secondary outcomes
Utility secondary outcome 1
Time frame: 5 years
Utility secondary outcome 2
Time frame: 5 years
Utility secondary outcome 3
Time frame: 5 years
Utility secondary outcome 4
Time frame: 5 years
Utility secondary outcome 5
Time frame: 5 years
Utility secondary outcome 6
Time frame: 5 years
Utility secondary outcome 7
Time frame: 5 years
Utility secondary outcome 8
Time frame: 5 years
Utility secondary outcome 9
Time frame: 5 years
Utility secondary outcome 10
Time frame: 5 years
Acceptability outcome 1
Time frame: 5 years
Acceptability outcome 2
Time frame: 5 years
Acceptability outcome 3
Time frame: 5 years
Acceptability outcome 4
Time frame: 5 years
Feasibility (ability of the study to be undertaken as designed) outcome 1
Time frame: 5 years
Feasibility (ability of the study to be undertaken as designed) outcome 2
Time frame: 5 years
Feasibility (ability of the study to be undertaken as designed) outcome 3
Time frame: 5 years
Feasibility (ability of the study to be undertaken as designed) outcome 4
Time frame: 5 years
Feasibility (ability of the study to be undertaken as designed) outcome 5
Time frame: 5 years
Cost effectiveness outcome 1
Time frame: 5 years
Cost effectiveness outcome 2
Time frame: 5 years
Cost effectiveness outcome 3
Time frame: 5 years
Cost effectiveness outcome 4
Time frame: 5 years
Accuracy outcome 1
Time frame: 5 years
Accuracy outcome 2
Time frame: 5 years
Utility secondary outcome 11
Time frame: 5 years
Feasibility outcome 6
Time frame: 5 years
Feasibility outcome 7
Time frame: 5 years
Utility secondary outcome 12
Time frame: 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Mar 2024.
- Derived from this study: PubMed 41238356Reimers R, Bailey M, Brown C, Chan K, Defay T, Finkel T, Kahn S, Protopsaltis L, Stoddard L, Talati AJ, Wigby K, Akil ASA, Wright M, Kingsmore SF; BeginNGS Consortium. Clinical utility and cost-effectiveness of BeginNGS newborn screening by genome sequencing and standard newborn screening for severe childhood genetic diseases: an adaptive, international and comparative clinical trial. BMJ Open. 2025 Nov 13;15(11):e098609. doi: 10.1136/bmjopen-2024-098609.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Stephen Kingsmore, MD DSc principal investigator
Rady Children's Institute for Genomic Medicine
Rebecca Reimers, MD MPH principal investigator
Rady Children's Institute for Genomic Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing BeginNGS Test in people with Genetic Disease, run by Rady Pediatric Genomics & Systems Medicine Institute at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 12 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Lauren Olsen, MSN (858-576-1700 ext. 228456, lolsen1@rchsd.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Comparison of the clinical utility of BeginNGS and standard of care (state NBS), defined by the proportion of enrollees likely to benefit (likely to have an improved outcome) from an indicated therapeutic intervention (time frame: 5 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06306521, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Mar 2024.