92 Confirmatory genetic testing for all CF screen positive newborns: a 12-year analysis
Bibliographic record
Abstract
Abstract Background Cystic fibrosis (CF) is an autosomal recessive disease that can present with multisystem manifestations based on mutations in the CF transmembrane regulator (CFTR) gene. Screening for CF was added to the Newborn Screening Ontario (NSO) program in 2008 using immunoreactive trypsinogen and genetic testing with a panel of 39 + 3 polymorphisms. From 2008-2020, our centre had all referred screen positive individuals undergo confirmatory genetic testing with an expanded panel of 70 + 4 polymorphisms, occasionally identifying a second mutation of varying clinical consequence. If an individual had a second mutation identified on our panel, prospective follow-up was offered. Objectives The aim of the study is to evaluate the utility of our expanded panel and subsequent identification of individuals with possible CFTR dysfunction. Design/Methods We conducted a retrospective descriptive analysis of our database of screen positive individuals, focusing on the subset who had a second mutation identified through expanded panel and whom we have offered clinical follow-up for 12 years. Results From 2008 to 2020, 718 screen positive individuals were referred to our CF Canada-accredited centre. 566 had one mutation identified by NSO. 94 of these had a second mutation identified on expanded panel. Of these, 13 had a sweat chloride between 30-60 mmol/L and 7 had a positive sweat test. Of those with borderline or negative sweats, 9 individuals continued to be followed. Two have converted to positive sweats, with 1 of these individuals requiring antibiotics for pulmonary exacerbations and the other remaining asymptomatic. Another 2 individuals are trending toward positive sweats (> 50 mmol/L). All spirometry values (FEV1, FVC) have been normal to date, and none have grown Pseudomonas aeruginosa. Conclusion Use of a confirmatory expanded panel identified a second mutation in 94 newborns referred with a positive screen. Offering follow-up has allowed us to monitor clinical progression, including conversion to positive sweats in 2 individuals. While spirometry and cultures have been unremarkable, more sensitive measures such as lung clearance index could be considered for future study. As of 2020, NSO moved to the use of extended sequencing and analysis of this change is ongoing.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".