LEARNING OBJECTIVES
After completing Module 2, the learner should be able to:
1. Estimate the effect of screening for islet autoantibodies and monitoring individuals at early-stage (presymptomatic)
T1D on rate of diabetic ketoacidosis at diagnosis of Stage 3 (symptomatic) T1D.
2. Describe groups of people who can benefit from screening for at early-stage (presymptomatic) T1D.
3. Describe the three types of screening programs for islet autoantibodies in the US and give one example for each.
Introduction to T1D Screening​
02 |
Module Authors: Cristy Geno, Brigitte Frohnert
FIGURE 1 Timeline and characteristics of the stages of T1D
Why Is Screening Important for Early-Stage Type 1 Diabetes (T1D)?
The American Diabetes Association has developed staging guidelines to describe the stages of T1D (see Module 1). Early stages of T1D (Stage 1 and Stage 2) are identified by measuring islet autoantibodies (IAb) in the blood and assessing for elevations in blood glucose. While individuals with both Stage 1 and Stage 2 T1D are presymptomatic, they differ by absence of glycemic abnormalities or evidence of dysglycemia, respectively (Figure 1). Stage 3 T1D represents individuals who are symptomatic and have hyperglycemia that meets standard criteria for diabetes.(1)
It is estimated that over 350,000 individuals in the U.S. are at high risk for developing symptomatic or Stage 3 T1D. In the U.S., over 50% of youth who are diagnosed at Stage 3 T1D present in diabetic ketoacidosis (DKA).(2) Population screening can identify individuals at early-stage T1D. Previous studies have shown that those who are identified at early-stage T1D, who receive education and monitoring, have a significantly lower rate of DKA than typical community-diagnosed cases, approximately 3 to 5 %. (3,4)
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Reducing the Risk of DKA Can Improve Outcomes.
DKA is life-threatening and associated with acute complications such as cerebral edema, renal injury, and electrolyte abnormalities. Long-term sequalae include memory and cognitive defects. Further, patients diagnosed with even mild or moderate DKA have higher average A1c over up to 15 years of follow-up.(5) It has long been appreciated that elevated A1c is associated with increased risk of complications across the life course. Screening for autoantibodies and monitoring can prevent >90% of DKA at diagnosis.(6) Previously published cost effectiveness analysis has shown screening is cost-effective, particularly when considering long-term impacts on health.(6)
Anticipatory Guidance and Risk Estimation
Approximately 3% of individuals who participate in autoantibody testing will screen positive for at least one islet autoantibody. The presence of two or more confirmed IAb in children is associated with an estimated incidence of developing Stage 3 T1D of 48% at 5 years, 75% at 10 years, and 88% at 15 years, with a lifetime risk approaching 100%.(7)
FIGURE 2
Progression from Stage 1 T1D
to Stage 3 T1D in children.
Prospective follow-up of 584 children from Finland, Germany, Sweden, and the U.S. with confirmed positive multiple IAb occurring at a mean age of 3.0 (IQR:1.8–5.9) years showed cumulative incidence of Stage 3 T1D of:
48% (95%CI: 42-50%) at 5 years;
75% (95%CI: 70–80%) at 10 years; and 88% (95%CI: 85–92%) at 15 years.
Adapted from Frohnert et al. 2023 (7)
48%
75%
88%
Importance of Screening in Individuals with NO Family History
In the United States, most individuals diagnosed with T1D (90%) do NOT have a history of T1D in a close family member.(8) Clinical symptoms of T1D may be overlooked as common illnesses and unrecognized in individuals who are not familiar with T1D signs and symptoms. Very young children and adults are most likely to have missed opportunities for diagnosis of T1D before correct diagnosis is ultimately considered. Further, individuals from historically marginalized groups and those with limited access to healthcare are more likely to present in DKA at time of diagnosis.(2)
Benefits of Early Diagnosis and Long-Term Disease Management
Beyond immediate and long-term reduction in morbidity, and financial burden, individuals who are diagnosed at early-stage T1D may be eligible for intervention trials to slow progression or the recently FDA-approved therapy, teplizumab-mzwv, which has the potential to delay the onset of clinical T1D by a median of 2 years. The ultimate goal of diagnosis at early-stage T1D is to facilitate personalized prediction, prevention, and preservation of beta-cell mass (see Modules 9 and 10).
Benefits of screening in adults with apparent prediabetes
or presumed type 2 diabetes
While most screening programs to date have focused on children, it is known that there are new diagnoses of Stage 3 T1D throughout adulthood.(9-11) While in fact, type 1 diabetes is diagnosed more frequently in adulthood, it is unfortunately commonly misdiagnosed as type 2 diabetes.(12,13) Proper diagnosis of adults is important not only to prevent ketoacidosis due to insulinopenia, but also because there are important differences in risk of diabetes-related complications depending on etiology of diabetes in adults.(13)
Availability of Autoantibody Testing
Clinical IAb testing has been available through commercial labs using a variety of assays (see Module 4) since 2005. Clinical IAb testing is commonly used to differentiate T1D from other diabetes types. In 2019, the ADA began recommending screening IAb panels in first-degree relatives of people with T1D, (14) and has since then expanded this recommendation to more broadly offer IAb panel screening to “those with a family history of type 1 diabetes or otherwise known elevated genetic risk.”(15) Clinically, islet autoantibody testing can be ordered as part of routine laboratory testing, particularly in those with autoimmunity or other high risk categories (see Module 3 for a discussion of high risk groups).
Autoantibody Screening Programs
In the United States, there are several screening initiatives and research programs which vary in their approach. TrialNet screens for islet autoantibodiesIAb in those with a family history of T1D or anyone who has previously been found to be islet autoantibody positive. Programs which screen individuals from the general population for IAb, without requirement for family history, include the Autoimmunity Screening for Kids (ASK) program and T1Detect. The PLEDGE program screens for both genetic risk score in the youngest children as well as for IAb at subsequent visits. Finally, some general population screening programs, such as Pr1Med, CASCADE, and the Early Check Study include genetic pre-screening for young children, followed by islet autoantibody screening targeted only to those at highest genetic risk (see Module 4). Ask the Experts is a program which provides information and support to individuals/families living in the United States who screen positive for early-stage T1D, as well as for health care providers seeking further information on managing and monitoring individuals with early T1D. It is not a screening program but can provide confirmation testing for those who have screened positive through other mechanisms.
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A family history of T1D — OR — a positive IAb on testing (outside of TrialNet)
are required for initial screening*:
TrialNet (USA)
*Those without family history but who have islet autoantibody positivity may also participate in TrialNet monitoring and clinical trials.
A family history of T1D NOT required:
ASK (USA) Barbara Davis Center for Diabetes
Ask the Experts (USA) Barbara Davis Center for Diabetes
PLEDGE Sanford Health
Screening Central Online Screening Request Portal
Genetic pre-screening before islet autoantibody testing:
Pr1MeD University of Virginia
CASCADE Pacific Northwest Research Institute
Early Check Study North Carolina
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