Clinical and genetic findings of individuals tested using the navigateAPDS genetic testing program
Bibliographic record
Abstract
BACKGROUND: Inborn errors of immunity (IEIs), including activated phosphoinositide-3-kinase delta syndrome (APDS), are underdiagnosed due to factors including heterogenous clinical manifestations, lack of awareness, and limited genetic testing access. Genetic testing may establish the molecular diagnosis (MolDx) of numerous IEIs, which may result in management changes. OBJECTIVE: To investigate the clinical utility of the navigateAPDS sponsored program established to increase MolDx of APDS through broad genetic testing. METHODS: The eligibility criteria to receive sponsored testing included APDS clinical features. RESULTS: Between March 2021 and September 2024, a total of 7811 patients across the United States and Canada underwent genetic testing. The median age at time of testing was 33 (range, 0-89) years, and the most selected eligibility criterion was severe, recurrent sinopulmonary infections. Of the 630 patients who received a positive MolDx, 377 (60%) had disorder-associated clinical actionability; 73 (12%) had Food and Drug Administration-approved treatments available. The most identified IEIs included genetically defined common variable immune deficiency and APDS. Of the patients with variants in PIK3CD or PIK3R1, 35 received an APDS MolDx and 131 received a variant of uncertain significance (VUS). Patients with APDS had a median age at time of symptom onset of 3 (range, 0-44) years and a median diagnostic delay of 13 (range, 0-50) years. Of the 13 APDS-causing variants identified, 5 were novel for APDS. CONCLUSION: These findings demonstrate that broad genetic testing for IEIs is useful and may contribute to disease management changes and improved health outcomes. Variant identification and VUS resolution are crucial in elucidating the genetic contribution to the clinical spectrum of IEIs and APDS.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.003 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".