Objective
We propose these steps: (a) using established virtual recruitment approaches and electronic consent to offer extra newborn screening (NBS) to babies of every birthing mother in North Carolina; (b) using genome sequencing to screen at least 10,000 newborns for panels of genes that are associated with single-gene conditions (including neonatal diabetes); (d) screening at least 5,000 newborns using a genetic risk score (GRS) for T1D that is calculated using the sequencing data; (e) providing diagnostic confirmation, genetic counseling, education, and follow-up for families of infants with positive or high-risk results; and (f) assessing key metrics that will inform future integration into state NBS, including feasibility, uptake and acceptability, and psychosocial impact of a higher risk/screen positive result on caregivers.
There are four aims for a single-gene sequencing pilot and four aims for the T1D screening pilot.
The aims of the single-gene sequencing project are the following:
• Aim 1: Use genetic sequencing to screen ~10,000 newborns for groups of single-gene conditions that can be found in young children.
• Aim 2: Determine how many parents decide to have their newborns screened, why they chose to screen their babies, and if the sign-up process, educational materials, and report of the screening results meet their needs.
• Aim 3: Monitor babies found to have these conditions over at least 12 months, provide families with education and support, and determine what parents need after learning this type of information.
• Aim 4: Assess the physical health of babies found to have these conditions and the mental health and attitudes of their caregivers.
The aims of the T1D screening project are the following:
• Aim 1: Determine what parents, primary care providers, specialists, and public health professionals think about using a genetic risk score in NBS to identify babies at higher risk for T1D.
• Aim 2: Use a genetic risk score to screen at least 5,000 newborns for increased risk for T1D.
• Aim 3: Monitor babies found to be at higher risk for T1D over at least 12 months, provide families with education and support, and determine what parents need after learning this type of information.
• Aim 4: Assess the physical health of babies found to be at higher risk for T1D and the mental health of their caregivers.
Background Rationale
Finding children with type 1 diabetes (T1D) early is important so that treatment can start right away to prevent serious complications of T1D. Currently, most children in the USA are not screened (checked for signs of a health problem before it starts) for T1D, and many are diagnosed only after serious complications of T1D have already started. One possible way to find children who may develop T1D later in life is through newborn screening (NBS). NBS is a state-run program that tests every baby at birth for a number of serious but treatable health conditions. To screen babies for T1D a new type of test called genetic sequencing (reading a baby’s genetic material or DNA) is needed. Genetic sequencing is not currently used by NBS programs to screen all babies, and research is needed to show that it works before NBS programs will consider adding it. Genetic sequencing can test babies for many, potentially hundreds, of different health conditions. Some health conditions are easier for sequencing to find than others. For example, there are several genes that can cause neonatal diabetes (NDM) but in any one baby NDM is caused by only one gene (called single-gene conditions). Babies found to have one of these genes will almost certainly get NDM. T1D is a trickier condition to find with sequencing than NMD as many different genes in combination may cause a child to get T1D. Genetic sequencing cannot tell us which babies will get T1D and which will not, it can only tell us which babies are more likely to get T1D as they get older. Something called a genetic risk score is needed to screen for T1D. A genetic risk score looks at markers in many different genes and can predict which babies are more likely to get T1D. Babies at higher risk for T1D can then be monitored by their doctor over time to check for signs that T1D may be starting. Since screening for T1D in babies using genetic sequencing is more complicated, when NBS programs eventually add genetic sequencing, it will likely be to screen for single-gene conditions (e.g., NMD) to start. However, the addition of genetic sequencing to NBS programs would be a victory for T1D screening, as that is the first step that needs to happen. Once genetic sequencing is added to NBS, it opens the door to screen for more complicated conditions like T1D. Early Check is a newborn screening research program that offers all parents in North Carolina extra screening for their baby for conditions that the state is currently not testing. The Early Check program allows us to show that the screening works and demonstrate how NBS programs could take it on. We propose a 3-year study to add genetic sequencing to Early Check to screen for both single-gene conditions and T1D. Doing so will help answer questions about how to safely and ethically add genetic sequencing to NBS in a way that is acceptable to both parents and health care providers. This study will also help us understand if parents want to know if their baby is at higher risk for T1D, what parents and health care providers do with that information if they choose to get it, and what families need after learning this information to best care for their babies. Early Check, and this proposed new study within Early Check, is run by RTI International with collaborators at the University of North Carolina at Chapel Hill (UNC-CH) and the North Carolina State Laboratory of Public Health (NCSLPH). This study will be the first of its kind in the USA.
Description of Project
Finding children with type 1 diabetes (T1D) early is important so that treatment can start right away to prevent serious complications of T1D. Currently, most children in the USA are not screened (checked for signs of a health problem before it starts) for T1D, and many are diagnosed only after serious complications of T1D have already started. One possible way to find children who may develop T1D later in life is through newborn screening (NBS). NBS is a state-run program that tests every baby at birth for a number of serious but treatable health conditions. To screen babies for T1D a new type of test called genetic sequencing (reading a baby’s genetic material or DNA) is needed. Genetic sequencing is not currently used by NBS programs to screen all babies, and research is needed to show that it works before NBS programs will consider adding it. Genetic sequencing can test babies for many, potentially hundreds, of different health conditions. Some health conditions are easier for sequencing to find than others. For example, there are several genes that can cause neonatal diabetes (NDM) but in any one baby NDM is caused by only one gene (called single-gene conditions). Babies found to have one of these genes will almost certainly get NDM. T1D is a trickier condition to find with sequencing than NMD as many different genes in combination may cause a child to get T1D. Genetic sequencing cannot tell us which babies will get T1D and which will not, it can only tell us which babies are more likely to get T1D as they get older. Something called a genetic risk score is needed to screen for T1D. A genetic risk score looks at markers in many different genes and can predict which babies are more likely to get T1D. Babies at higher risk for T1D can then be monitored by their doctor over time to check for signs that T1D may be starting. Since screening for T1D in babies using genetic sequencing is more complicated, when NBS programs eventually add genetic sequencing, it will likely be to screen for single-gene conditions (e.g., NMD) to start. However, the addition of genetic sequencing to NBS programs would be a victory for T1D screening, as that is the first step that needs to happen. Once genetic sequencing is added to NBS, it opens the door to screen for more complicated conditions like T1D. Early Check is a newborn screening research program that offers all parents in North Carolina extra screening for their baby for conditions that the state is currently not testing. The Early Check program allows us to show that the screening works and demonstrate how NBS programs could take it on. We propose a 3-year study to add genetic sequencing to Early Check to screen for both single-gene conditions and T1D. Doing so will help answer questions about how to safely and ethically add genetic sequencing to NBS in a way that is acceptable to both parents and health care providers. This study will also help us understand if parents want to know if their baby is at higher risk for T1D, what parents and health care providers do with that information if they choose to get it, and what families need after learning this information to best care for their babies. Early Check, and this proposed new study within Early Check, is run by RTI International with collaborators at the University of North Carolina at Chapel Hill (UNC-CH) and the North Carolina State Laboratory of Public Health (NCSLPH). This study will be the first of its kind in the USA.
Anticipated Outcome
The project will generate much-needed data on the feasibility and acceptability of using genetic sequencing and genetic risk scores for T1D in newborn screening (NBS). We propose to start by offering this type of NBS under a research study so parents can decide whether they want their child to have the screening. Later, if genetic sequencing and the use of genetic risk scores were put into standard state NBS, in most states parents do not have to agree for their child to have NBS. Blood for NBS is taken in the hospital or birthing center unless parents specifically ask for it not to be done. This makes it especially important that we conduct pilot studies so we can understand whether new types of NBS work well enough and whether parents and clinicians find the screening acceptable. Basically, we need to start with a study where parents are able to make a choice about screening. Then we may find data that suggest that new types of NBS are important to babies’ health and acceptable to most parents. We also need data from research to show that the laboratory screening, reporting, and follow up can reasonably be done. These types of data are needed to make the case to policymakers and other stakeholders on whether genetic sequencing and genetic risk scores for T1D can reasonably and ethically be used in NBS.
At the end of the study, we will have the following:
• A proven framework directly relevant for policy makers to evaluate the appropriateness of genetic sequencing for NBS, with sufficient rigor and flexibility to enable us to add new conditions as additional data, discoveries, and treatments emerge.
• An implementation model for the addition of genetic risk for a complex disorder to NBS, which takes into account the complexities of screening for susceptibility to T1D.
• A clear understanding of components and quality metrics for each step in the sequencing pipeline, genetic risk score calculation, and the prevalence of newborns with higher risk screening results.
• Documentation of the acceptability of using sequencing to screen for single-gene conditions and susceptibility to T1D.
• Detailed protocols for education, counseling, and follow-up for children at higher risk for T1D that are appropriate for implementation in NBS, and protocols that support pediatricians and other clinicians across the state to provide appropriate care for children and their families.
• Documentation of at least 1-year outcomes for children at higher risk for T1D and their families, while developing a cohort of children that can be followed long-term.
Relevance to T1D
A major goal of this project is to inform the use of genetic risk scores in newborn screening (NBS) to screen for T1D. Early identification of children with increased genetic risk for T1D permits parental and health care provider education, autoantibody testing, early treatment, and access to appropriate clinical research. Population-based genomic screening in young children provides an equitable approach that may be most effective at reducing later health problems that can be caused by T1D. The timing of such screening is an area of active debate. Some studies and recommendations focus on screening in young children; this approach may miss the earliest onset, most severe cases. Screening through primary care raises many barriers related to health care provider training, reimbursement, education, and follow-up. In addition, in the United States, it is difficult to achieve equal access for screening when it is done in pediatric primary care settings. In contrast, NBS is a well-established and successful public health program that is already available to all babies born in all U.S. states. Integrating T1D risk screening into NBS may be the most effective approach to identifying babies at higher genetic risk and intervening early. But pilot studies are needed to provide data about the use of screening for T1D in public health NBS.