Articles
Two-age islet-autoantibody screening for childhood type 1 diabetes: a prospective cohort study

https://doi.org/10.1016/S2213-8587(22)00141-3Get rights and content

Summary

Background

Early prediction of childhood type 1 diabetes reduces ketoacidosis at diagnosis and provides opportunities for disease prevention. However, only highly efficient approaches are likely to succeed in public health settings. We sought to identify efficient strategies for initial islet autoantibody screening in children younger than 15 years.

Methods

We harmonised data from five prospective cohorts from Finland (DIPP), Germany (BABYDIAB), Sweden (DiPiS), and the USA (DAISY and DEW-IT) into the Type 1 Diabetes Intelligence (T1DI) cohort. 24 662 children at high risk of diabetes enrolled before age 2 years were included and followed up for islet autoantibodies and diabetes until age 15 years, or type 1 diabetes onset, whichever occurred first. Islet autoantibodies measured included those against glutamic acid decarboxylase, insulinoma antigen 2, and insulin. Main outcomes were sensitivity and positive predictive value (PPV) of detected islet autoantibodies, tested at one or two fixed ages, for diagnosis of clinical type 1 diabetes.

Findings

Of the 24 662 participants enrolled in the Type 1 Diabetes Intelligence cohort, 6722 total were followed up to age 15 years or until onset of type 1 diabetes. Type 1 diabetes developed by age 15 years in 672 children, but did not develop in 6050 children. Optimal screening ages for two measurements were 2 years and 6 years, yielding sensitivity of 82% (95% CI 79–86) and PPV of 79% (95% CI 75–80) for diabetes by age 15 years. Autoantibody positivity at the beginning of each test age was highly predictive of diagnosis in the subsequent 2–5·99 year or 6–15-year age intervals. Autoantibodies usually appeared before age 6 years even in children diagnosed with diabetes much later in childhood.

Interpretation

Our results show that initial screening for islet autoantibodies at two ages (2 years and 6 years) is sensitive and efficient for public health translation but might require adjustment by country on the basis of population-specific disease characteristics.

Funding

Juvenile Diabetes Research Foundation.

Introduction

Islet autoantibodies are useful biomarkers of future type 1 diabetes, although the time from the appearance of autoimmunity to clinical diagnosis is highly variable (ie, from weeks to decades). In young children, especially those younger than 6 years, many studies have shown that most diabetic ketoacidosis at onset of type 1 diabetes can be prevented by surveillance of islet autoantibodies, with subsequent patient education and monitoring of deteriorating glucose metabolism.1, 2 Prevention therapy to delay the clinical onset of type 1 diabetes in people with islet autoantibodies was also shown to be successful in a trial of teplizumab.3 The prospective study of children at preclinical stages of type 1 diabetes is also essential to refine markers of progression, and to better understand disease mechanisms.

Both genetic screening and islet-autoantibody surveillance have become less expensive4, 5 and have been shown to be accurate in predicting type 1 diabetes.6, 7 However, substantial challenges must be met before public health adoption of population-wide prediction of paediatric type 1 diabetes. To prevent the most severe cases of diabetic ketoacidosis and to provide opportunity for prevention therapy to delay the onset of clinical diabetes, islet-autoantibody detection must occur early enough in life to precede the highest incidence period between age 2 years and 15 years. Childhood type 1 diabetes is a severe disease, but its incidence of approximately 1 in 300 children is low enough that decreasing diabetic ketoacidosis, delaying onset of hyperglycaemia, and improving disease course after onset together yield only moderate aggregate medical cost savings. To achieve commensurate low costs for a prediction programme, highly efficient strategies with limited testings are needed.8 Prescreening using advances in genetic risk assessment can greatly improve efficiency4 by defining a high risk subset, but efficient initial islet autoantibody testing also has a key role. Fewer tests inevitably bring sensitivity losses, therefore it is essential to optimise initial screening strategies to maximise sensitivity. After the screening is completed, subsequent follow-up autoantibody surveillance testing with greater specificity might then lead to glycaemic monitoring, education on symptoms to prevent diabetic ketoacidosis, and consideration of prevention therapy.

Research in context

Evidence before this study

To search for the evidence published before this study, we searched PubMed using the search terms “pediatric islet autoantibodies”, “public health screening islet autoantibodies”, and “population-based prediction of type 1 diabetes” for articles published between Jan 1, 2012, and May 1, 2022 (date of last search). Most childhood type 1 diabetes cases appear in people with high HLA genetic risk, but about a quarter of cases have lower HLA risk. Islet autoantibodies are known to precede diagnosis and can reveal people at greatest future risk of type 1 diabetes. Knowing islet autoantibodies status in advance can prevent most diabetic ketoacidosis at onset, and immunotherapy applied in individuals who are islet autoantibodies positive can significantly delay onset. Multiple-islet autoantibodies mark the greatest risk as do islet autoantibodies appearing in early childhood. However, autoimmunity might evolve over time, and people initially with single-islet autoantibodies, or with islet autoantibodies appearing later in childhood, can also progress to clinical disease. Most large studies to date have followed up children at high HLA or familial risk via frequent islet autoantibodies testing throughout childhood. Although sensitive and specific, these approaches are not cost-effective for prediction of population-wide type 1 diabetes.

Added value of this study

Our results show that testing at only two ages (2 years and 6 years) is sufficient to detect a large majority of cases occurring by age 15 years. We found that including children who were positive for single-islet autoantibodies provided a key part of this sensitivity, especially children younger than 6 years. Our results, although primarily from children who were prescreened for elevated genetic risk, suggest that this strategy might apply even in those at lower HLA risk. Another key finding was that two-age islet-autoantibody testing might have different optimal ages in different geographical regions.

Implications of all the available evidence

Our results show that an efficient, initial autoantibody testing strategy might be sufficient in predicting type 1 diabetes diagnosis before the age of 15 years and raises the possibility that similar population-wide screening for future type 1 diabetes is possible.

The Type 1 Diabetes Intelligence (T1DI) study9 offers a uniquely large and harmonised dataset combining several birth-cohort studies that tested children frequently through adolescence. Using T1DI, we sought to identify optimum testing strategies to identify paediatric islet autoantibody to efficiently reveal future risk of type 1 diabetes, ultimately for translation to public health and medical care.

Section snippets

Study design and cohort

The T1DI prospective cohort study9 incorporated participants from five prospective longitudinal cohorts: the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study;10 the Swedish Diabetes Prediction in Skåne Study (DiPiS);11 the Diabetes Autoimmunity Study in the Young (DAISY) from Colorado, USA;12 the Diabetes Evaluation in Washington (DEW-IT) from Washington State, USA;13 and BABYDIAB from Germany.14 Local institutional review board approval, parental informed consent, and child

Results

A total of 24 662 participants were followed up from early childhood (DIPP n=11 652 [47%] of 24 662; DiPiS n=4359 [18%]; DAISY n=2539 [10%]; DEW-IT n=3748 [15%]; BABYDIAB n=2364 [10%]) and of these 6722 total (3605 female participants) were followed up to age 15 years or until onset of type 1 diabetes. These participants included 6050 children who did not develop type 1 diabetes and 672 who were diagnosed with type 1 diabetes by age 15 years (appendix p 3). Overall, about 74% of the cohort did

Discussion

Early detection of islet autoantibodies in children has been widely shown to prevent diabetic ketoacidosis at diagnosis1, 2 and provides an opportunity to apply prevention therapies.3 For this reason, islet-autoantibody screening strategies have been extensively studied in paediatric populations.18, 19 However, the relatively low prevalence of type 1 diabetes makes it difficult to accomplish paediatric screening at a cost acceptable for public health translation.8, 20 The combined T1DI cohort

Data sharing

The data supporting these study findings are available through the Type 1 Diabetes Intelligence Consortium upon reasonable request to the corresponding author. The data are not publicly available because of privacy regulations.

Declaration of interests

MG and VA are employees of IBM. JLD did this work as an employee of the Juvenile Diabetes Research Foundation and is now an employee of Janssen Research and Development. All other authors declare no competing interests.

References (30)

  • A Kupila et al.

    Feasibility of genetic and immunological prediction of type I diabetes in a population-based birth cohort

    Diabetologia

    (2001)
  • HE Larsson

    A Swedish approach to the prevention of type 1 diabetes

    Pediatr Diabetes

    (2016)
  • M Rewers et al.

    Newborn screening for HLA markers associated with IDDM: diabetes autoimmunity study in the young (DAISY)

    Diabetologia

    (1996)
  • E Wion et al.

    Population-wide infant screening for HLA-based type 1 diabetes risk via dried blood spots from the public health infrastructure

    Ann NY Acad Sci

    (2003)
  • AG Ziegler et al.

    Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study

    Diabetes

    (1999)
  • Cited by (15)

    • Teplizumab approval for type 1 diabetes in the USA

      2023, The Lancet Diabetes and Endocrinology
    • Impact of the COVID-19 pandemic on long-term trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes: an international multicentre study based on data from 13 national diabetes registries

      2022, The Lancet Diabetes and Endocrinology
      Citation Excerpt :

      Consequently, universal efforts are needed to reverse the increasing trend of diabetic ketoacidosis worldwide. For instance, educational campaigns have been effective in raising awareness of the symptoms of diabetes, and screening programmes for islet autoantibodies aimed at reducing the incidence of diabetic ketoacidosis at diagnosis of diabetes have been reported.24,25 We found a significant association between the likelihood of diabetic ketoacidosis at type 1 diabetes diagnosis and the pandemic containment measures, as expressed by the Stringency Index.

    • On the road to universal screening for risk of type 1 diabetes

      2022, The Lancet Diabetes and Endocrinology
    View all citing articles on Scopus

    Members of the Type 1 Diabetes Intelligence Study Group are listed at the end of the paper

    View full text