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TrialNet Pathway to Prevention

Type 1 Diabetes TrialNet (NIH/NIDDK-funded consortium; coordinated by University of South Florida)

Free screening for relatives.

What it is

Free, NIH-funded islet-autoantibody screening for relatives of people with T1D, with long-term monitoring and trial referral for those who screen positive. Detects presymptomatic (stage 1/2) T1D, which lowers ketoacidosis at diagnosis and opens the door to therapy like teplizumab — but, being relative-focused, it reaches only the ~10% of future cases that have a family history.

Editorial review: .

Source dates appear in the references where available; this record has no dated citation metadata.

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Available nowStrong evidenceautoantibodyscreeningrelative-focusedfreelongitudinal-monitoringtrial-gatewaypresymptomaticstaginggadia-2znt8capillary-or-venousnih-funded

Evidence behind this assessment

Key evidence notes. Study results, product eligibility and access answer different questions.

Who was studied?
Study populations and analysis groups vary. Product age limits alone do not describe who was studied.
Benefit or performance
Predictive value: Autoantibody count is a powerful, validated predictor: 10-year progression after seroconversion was 69.7% with multiple antibodies vs 14.5% with a single antibody and 0.4% with none (Ziegler 2013); two-plus antibodies define stage 1 disease by consensus (Insel 2015).Read the supporting discussion; this assessment has no individually linked citation.
Important harms and treatment burden
Read the safety discussion and original sources. A missing summary does not establish safety.
Approval and country access
Free autoantibody screening and staged monitoring for relatives of people with T1DApproval, trial recruitment, local supply and funding are separate. Check the cited label or access source.
Follow-up and remaining uncertainty
Read the full discussion and original sources for follow-up duration and study limitations.
Editorial score: calculation and evidence

A weighted editorial judgment on a 0–100 scale, not a probability of success or a measured treatment effect. Higher criterion scores mean more favorable assessments.

Default calculation: 90 × 25 + 85 × 25 + 35 × 20 + 70 × 15 + 80 × 15 = 7325; divide by total weight 100. Unrounded weighted result: 73.25.

Predictive value90

Autoantibody count is a powerful, validated predictor: 10-year progression after seroconversion was 69.7% with multiple antibodies vs 14.5% with a single antibody and 0.4% with none (Ziegler 2013); two-plus antibodies define stage 1 disease by consensus (Insel 2015).

Actionability85

Positive screen triggers metabolic monitoring that nearly eliminates DKA at onset (zero DKA in the San Raffaele TrialNet cohort, Martinenghi 2025) and routes stage-2 relatives to teplizumab, FDA-approved 2022 after the TrialNet TN-10 trial delayed stage 3 by a median ~24 months (Herold 2019).

Reach35

Eligibility is essentially limited to relatives (plus known-antibody-positive non-relatives), yet ~90% of new T1D occurs in people with no family history, so the relative-focused design structurally misses most future cases — the gap general-population programs aim to close.

Low burden70

Screening is a single blood test for islet autoantibodies that can be done via a mailed kit taken to a local lab; positive participants then need periodic in-person OGTT-based monitoring, though modeling shows visit frequency can be roughly halved without raising DKA risk (O'Rourke 2023).

Access & cost80

Fully free to eligible participants and available across a large NIH-funded international network (US, Canada, UK, Sweden, Finland, Germany, Italy, Australia, New Zealand); ceiling is set by relative-only eligibility and the need to live near or mail to a participating site.

The full picture

What TrialNet Pathway to Prevention is

Pathway to Prevention (also called the TrialNet Natural History Study, ClinicalTrials.gov NCT00097292) is a long-running, NIH/NIDDK-funded program that offers free islet-autoantibody screening to relatives of people with type 1 diabetes (T1D), then follows those who test positive with long-term monitoring and refers them to prevention trials.12 TrialNet was established in 2001 and has screened more than 235,000 relatives through an international network of clinical centers and affiliate sites in the US, Canada, UK, Sweden, Finland, Germany, Italy, Australia and New Zealand.23

The screening: what is measured

A simple blood test looks for islet autoantibodies — the immune "fingerprints" of T1D — against up to five targets: GAD65 (GADA), insulin (mIAA), IA-2 (IA-2A), zinc transporter 8 (ZnT8A) and islet cells (ICA).3 About 5% of screened relatives carry one or more.3 You don't have to visit a center: TrialNet can mail a kit to take to a local lab.1

The staging model — why antibody count matters

T1D progresses through defined stages before symptoms: stage 1 is two or more autoantibodies with normal blood sugar; stage 2 is two or more autoantibodies with dysglycemia; stage 3 is clinical diabetes.4 A landmark pooled study showed how predictive this is: 10 years after seroconversion, 69.7% of children with multiple autoantibodies had progressed to diabetes, versus 14.5% with a single antibody and 0.4% with none.5 So a positive screen is genuinely informative — and increasingly actionable.

Who to screen, and the reach problem

Eligibility is broad among relatives: ages 2-45 with a parent, sibling or child who has T1D, and ages 2-20 with an extended relative (grandparent, aunt/uncle, cousin, niece/nephew, half-sibling); known antibody-positive non-relatives can also enroll.12 The catch: roughly 90% of people who develop T1D have no family history, so a relative-only program, by design, never sees most future cases — the central argument for general-population screening.6

What early detection enables

Identifying presymptomatic T1D and then monitoring changes outcomes. In a single-center TrialNet cohort in Italy, autoantibody screening plus regular monitoring completely prevented diabetic ketoacidosis at diagnosis (median venous pH 7.37, zero DKA), with 15-year diabetes-free survival of 45.9% in multiple-antibody-positive vs 87.3% in single-positive participants.7 Modeling suggests this DKA benefit can be achieved at the population level with roughly half the usual monitoring visits, easing burden.8

Therapy access — the payoff

Crucially, screening is the gateway to disease-modifying therapy. TrialNet's TN-10 trial gave the anti-CD3 antibody teplizumab to stage-2 relatives identified through this very pathway; median time to clinical diabetes was 48.4 vs 24.4 months (hazard ratio 0.41), a delay of roughly two years.9 On that basis the FDA approved Tzield (teplizumab) in 2022 for ages 8+ with stage 2 T1D — described in the FDA approval announcement as the first drug to delay T1D onset.10

What's coming

In April 2026 the FDA expanded Tzield to children as young as age 1, widening who benefits from an early diagnosis.11 Research is also refining who needs how much monitoring: combined genetic-risk-score, age and antibody models (validated in TrialNet) now tailor risk prediction and cost, pointing toward cheaper, lighter-touch surveillance and a future where screening reaches beyond relatives into the general population.1213

What's next for this

  • →FDA expanded Tzield (teplizumab) to children as young as age 1, widening who benefits from early diagnosis · April 2026
  • →Combined genetic-risk-score, age and antibody models tailoring risk prediction toward cheaper, lighter-touch surveillance

Sources

  1. [1]

    Type 1 Diabetes TrialNet. Pathway to Prevention (Risk Screening). trialnet.org (accessed 2026). https://www.trialnet.org/our-research/risk-screening

  2. [2]

    NIH / University of South Florida. TrialNet Pathway to Prevention of T1D. ClinicalTrials.gov NCT00097292 (accessed 2026). https://clinicaltrials.gov/study/NCT00097292

    TrialNet Pathway to Prevention of T1D — eligibility (ages 2-45 first-degree; 2-20 extended relatives; antibody-positive non-relatives). ClinicalTrials.gov NCT00097292 (accessed 2026). https://clinicaltrials.gov/study/NCT00097292

  3. [3]

    Battaglia M, et al. Type 1 Diabetes TrialNet: A Multifaceted Approach to Bringing Disease-Modifying Therapy to Clinical Use. Diabetes Care / PMC (2018). https://pmc.ncbi.nlm.nih.gov/articles/PMC5860837/

  4. [4]

    Insel RA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the ADA. Diabetes Care (2015). https://doi.org/10.2337/dc15-1419

  5. [5]

    Ziegler AG, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA (2013). https://doi.org/10.1001/jama.2013.6285

  6. [6]

    Templeman EL, et al. Contrasting adult and pediatric populations in the TrialNet Pathway to Prevention study (235,709 relatives screened; basis for relative-vs-general-population reach). Diabetes Care (2025). https://doi.org/10.2337/dc25-0192

  7. [7]

    Martinenghi S, et al. Prevention of diabetic ketoacidosis in relatives screened for islet autoantibodies in TrialNet Pathway to Prevention at a single institution in Italy. Diabetologia (2025). https://doi.org/10.1007/s00125-025-06461-z

  8. [8]

    O'Rourke C, et al. Risk modeling to reduce monitoring of an autoantibody-positive population to prevent DKA at type 1 diabetes diagnosis. J Clin Endocrinol Metab (2023). https://doi.org/10.1210/clinem/dgac594

  9. [9]

    Herold KC, et al. An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes (TN-10). N Engl J Med (2019). https://doi.org/10.1056/NEJMoa1902226

  10. [10]

    U.S. Food and Drug Administration. FDA approves first drug that can delay onset of type 1 diabetes (FDA Update, Jan 1, 2023; original approval Nov 17, 2022). https://www.fda.gov/media/164864/download

  11. [11]

    U.S. Food and Drug Administration. TZIELD (teplizumab-mzwv) prescribing information. FDA (2026 label; stage-2 delay indication in adults and pediatric patients 1 year and older). https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/761183s013lbl.pdf

  12. [12]

    Ferrat LA, et al. Type 1 diabetes prediction in autoantibody-positive individuals: performance, time and money matter (TrialNet PTP cohort). Diabetologia (2025). https://doi.org/10.1007/s00125-025-06434-2

  13. [13]

    Templeman EL, et al. Development and recalibration of a multivariable type 1 diabetes prediction model across screening studies (TEDDY + TrialNet). BMC Medicine (2025). https://doi.org/10.1186/s12916-025-04225-5