Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project.

Newborn screening (NBS) was established as a public health program in the 1960s and is crucial for facilitating detection of certain medical conditions in which early intervention can prevent serious, life-threatening health problems. Genomic sequencing can potentially expand the screening for rare hereditary disorders, but many questions surround its possible use for this purpose. We examined the use of exome sequencing (ES) for NBS in the North Carolina Newborn Exome Sequencing for Universal Screening (NC NEXUS) project, comparing the yield from ES used in a screening versus a diagnostic context. We enrolled healthy newborns and children with metabolic diseases or hearing loss (106 participants total). ES confirmed the participant's underlying diagnosis in 15 out of 17 (88%) children with metabolic disorders and in 5 out of 28 (∼18%) children with hearing loss. We discovered actionable findings in four participants that would not have been detected by standard NBS. A subset of parents was eligible to receive additional information for their child about childhood-onset conditions with low or no clinical actionability, clinically actionable adult-onset conditions, and carrier status for autosomal-recessive conditions. We found pathogenic variants associated with hereditary breast and/or ovarian cancer in two children, a likely pathogenic variant in the gene associated with Lowe syndrome in one child, and an average of 1.8 reportable variants per child for carrier results. These results highlight the benefits and limitations of using genomic sequencing for NBS and the challenges of using such technology in future precision medicine approaches.

Impact of Hurricane Matthew on Diabetes Self-Management and Outcomes.

BACKGROUND: Individuals with diabetes require extensive self-management. Little is known about how Hurricane Matthew (Matthew) or Hurricane Florence (Florence) impacted diabetes self-management and outcomes in Robeson County, North Carolina. METHODS: Mixed methods were used to assess the impact of hurricanes on diabetes self-management and outcomes. Individuals with diabetes were recruited for focus groups to understand the perceived impact on diabetes self-management. Health care providers were recruited for parallel key informant interviews. Mean hemoglobin A1c (HbA1c) and frequency of diabetic ketoacidosis (DKA) from hospital data six months before and after Matthew were compared using Student t-tests. RESULTS: A demographic breakdown of 34.25% white, 21.70% Black or African American, and 21.38% American Indian or Alaska Native was observed from focus groups. Qualitative results highlight a limited access to a balanced diet and medications. No significant differences were found between mean HbA1c values before and after Matthew (before Matthew: mean HbA1c 8.34 ± 1.87%; after Matthew: mean HbA1c 8.31 ± 1.93 %; P = .366). The period prevalence (PP) of DKA was higher after Matthew than before (before Matthew: 39 cases out of 4,025 visits, PP = .010; after Matthew: 87 cases out of 3,779 visits, PP = .023; P <.0001). LIMITATIONS: Limitations include non-random sampling and limited sample sizes. Also, the cross-sectional panel approach did not follow the same individuals over time. CONCLUSIONS: The period prevalence of DKA was higher in the six-month time period following Matthew compared to before the hurricane. Future interventions may improve outcomes via increased access to foods and medications recommended for those with diabetes.

The interplay of type 1 diabetes and weight management: A qualitative study exploring thematic progression from adolescence to young adulthood.

BACKGROUND: The impact of weight management in persons with type 1 diabetes (T1D) from childhood into adulthood has not been well described. The purpose of the study was to explore qualitative themes presented by young adults with T1D with respect to the dual management of weight and T1D. METHODS: We analyzed focus group data from 17 young adults with T1D (65% female, age 21.7 ± 2.1 years, HbA1c 8.1% ± 1.5) via inductive qualitative analysis methods. Major themes were compared to themes presented by youth with T1D ages 13-16 years in previously published study in order to categorize thematic progression from early adolescence through adulthood. RESULTS: Themes from young adults with T1D, when compared to those from youth were categorized as: (a) persistent and unchanged themes, (b) evolving themes, and (c) newly reported themes. Hypoglycemia and a sense of futility around exercise was an unchanged theme. Importance of insulin usage and a healthy relationship with T1D evolved to gather greater conviction. Newly reported themes are unique to integration of adulthood into T1D, such as family planning and managing T1D with work obligations. Young adults also reported negative experiences with providers in their younger years and desire for more supportive provider relationships. CONCLUSIONS: Issues identified by youth regarding the dual management of T1D and weight rarely resolve, but rather, persist or evolve to integrate other aspects of young adulthood. Individualized and age-appropriate clinical support and practice guidelines are warranted to facilitate the dual management of weight and T1D in persons with T1D.

Design of the Advancing Care for Type 1 Diabetes and Obesity Network energy metabolism and sequential multiple assignment randomized trial nutrition pilot studies: An integrated approach to develop weight management solutions for individuals with type 1 diabetes.

Young adults with type 1 diabetes (T1D) often have difficulty co-managing weight and glycemia. The prevalence of overweight and obesity among individuals with T1D now parallels that of the general population and contributes to dyslipidemia, insulin resistance, and risk for cardiovascular disease. There is a compelling need to develop a program of research designed to optimize two key outcomes-weight management and glycemia-and to address the underlying metabolic processes and behavioral challenges unique to people with T1D. For an intervention addressing these dual outcomes to be effective, it must be appropriate to the unique metabolic phenotype of T1D, and to biological and behavioral responses to glycemia (including hypoglycemia) that relate to weight management. The intervention must also be safe, feasible, and accepted by young adults with T1D. In 2015, we established a consortium called ACT1ON: Advancing Care for Type 1 Diabetes and Obesity Network, a transdisciplinary team of scientists at multiple institutions. The ACT1ON consortium designed a multi-phase study which, in parallel, evaluated the mechanistic aspects of the unique metabolism and energy requirements of individuals with T1D, alongside a rigorous adaptive behavioral intervention to simultaneously facilitate weight management while optimizing glycemia. This manuscript describes the design of our integrative study-comprised of an inpatient mechanistic phase and an outpatient behavioral phase-to generate metabolic, behavioral, feasibility, and acceptability data to support a future, fully powered sequential, multiple assignment, randomized trial to evaluate the best approaches to prevent and treat obesity while co-managing glycemia in people with T1D. Clinicaltrials.gov identifiers: NCT03651622 and NCT03379792. The present study references can be found here: https://clinicaltrials.gov/ct2/show/NCT03651622 https://clinicaltrials.gov/ct2/show/NCT03379792?term=NCT03379792&draw=2&rank=1 Submission Category: "Study Design, Statistical Design, Study Protocols".

Trends in Glycemia between 2002 and 2016 among Incident Youth Cohorts Early in the Course of Type 1 Diabetes: The SEARCH for Diabetes in Youth Study.

Objective: Hyperglycemia early in the course of type 1 diabetes (T1D) may increase the risk of cardiometabolic complications later in life. We tested the hypothesis that there were temporal trends in population-level glycemia and insulin pump use near T1D diagnosis among incident youth cohorts diagnosed between 2002 and 2016. Methods: Weighted and adjusted regression models were applied to data from the SEARCH for Diabetes in Youth study to analyze trends in hemoglobin A1c (HbA1c), suboptimal glycemia (HbA1c > 9% or not), and insulin pump use among youth with T1D within 30 months of diagnosis. We tested the interaction of year with race and ethnicity, sex, and insulin regimen to assess potential disparities. Results: Among the 3,956 youth with T1D, there was a small, clinically insignificant reduction in HbA1c between 2002 (7.9% ± 1.5) and 2016 (7.8% ± 2.4) (fully adjusted change by year (-0.013% [95% CI -0.026, -0.0008], p = 0.04). The proportion of youth with suboptimal glycemia increased with each year, but the adjusted odds did not change. Insulin pump use increased more than fivefold. Although interaction effects of time with race and ethnicity, sex, and insulin regimen were not detected, in 2016, suboptimal glycemia was 4.3 and 1.8 times more prevalent among Black and Hispanic than among non-Hispanic White youth, respectively. Conclusions: There was not a clinically significant population-level improvement in glycemia across incident youth cohorts early in the course of T1D, despite severalfold increases in insulin pump use. Comprehensive clinical interventions to improve glycemia early in the T1D course and address disparities are urgently needed.

'La Vida Normal': Young people adapting to Type 1 diabetes in Bolivia.

OBJECTIVES: To identify challenges and coping strategies of young people with Type 1 diabetes (T1D) and their families in Bolivia through qualitative analysis of interviews with beneficiaries of Centro Vivir con Diabetes (CVCD), a diabetes health center supported by the International Diabetes Federation Life for a Child (LFAC) program. METHODS: Eighteen young people aged 14-33 and at least one caregiver participated in semi-structured interviews in five cities in Bolivia from May to June 2016. Interviews were recorded, transcribed, and analyzed using inductive thematic analysis. RESULTS: Participants described needing guidance at diagnosis and facing stigma in communities. Young people expressed that life with T1D was 'la vida normal' (a normal life), although interpretations of normalcy varied. For some, 'la vida normal' meant resistance to T1D; for others it indicated acceptance. DISCUSSION: Access to interdependent spheres of support allowed young people to form a new normal around T1D. Receiving supplies through the CVCD/LFAC partnership maintained family connection to clinical care, CVCD education helped families share in T1D management, and peer support mitigated stigma for young people. Programs like CVCD that combine supply-based aid with clinical education for whole families, create effective support for young people with T1D in low- and middle-income countries.

Evaluating parents' decisions about next-generation sequencing for their child in the NC NEXUS (North Carolina Newborn Exome Sequencing for Universal Screening) study: a randomized controlled trial protocol.

BACKGROUND: Using next-generation sequencing (NGS) in newborn screening (NBS) could expand the number of genetic conditions detected pre-symptomatically, simultaneously challenging current precedents, raising ethical concerns, and extending the role of parental decision-making in NBS. The NC NEXUS (Newborn Exome Sequencing for Universal Screening) study seeks to assess the technical possibilities and limitations of NGS-NBS, devise and evaluate a framework to convey various types of genetic information, and develop best practices for incorporating NGS-NBS into clinical care. The study is enrolling both a healthy cohort and a cohort diagnosed with known disorders identified through recent routine NBS. It uses a novel age-based metric to categorize a priori the large amount of data generated by NGS-NBS and interactive online decision aids to guide parental decision-making. Primary outcomes include: (1) assessment of NGS-NBS sensitivity, (2) decision regret, and (3) parental decision-making about NGS-NBS, and, for parents randomized to have the option of requesting them, additional findings (diagnosed and healthy cohorts). Secondary outcomes assess parents' reactions to the study and to decision-making. METHODS/DESIGN: Participants are parents and children in a well-child cohort recruited from a prenatal clinic and a diagnosed cohort recruited from pediatric clinics that treat children with disorders diagnosed through traditional NBS (goal of 200 children in each cohort). In phase 1, all parent participants use an online decision aid to decide whether to accept NGS-NBS for their child and provide consent for NGS-NBS. In phase 2, parents who consent to NGS-NBS are randomized to a decision arm or control arm (2:1 allocation) and learn their child's NGS-NBS results, which include conditions from standard (non-NGS) NBS plus other highly actionable childhood-onset conditions. Parents in the decision arm use a second decision aid to make decisions about additional results from their child's sequencing. In phase 3, decision arm participants learn additional results they have requested. Online questionnaires are administered at up to five time points. DISCUSSION: NC NEXUS will use a rigorous interdisciplinary approach designed to collect rich data to inform policy, practice, and future research. TRIAL REGISTRATION: clinicaltrials.gov, NCT02826694 . Registered on 11 July, 2016.