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Cystic Fibrosis Screening Efficacy and Seasonal Variation in California: 15-Year Comparison of IRT Cutoffs Versus
Stanley Sciortino1, Steve Graham1, Tracey Bishop1
1Genetic Disease Screening Program, California Department of Public Health, Richmond, CA 94804, USA.
Insights
Seasonal variations impact newborn screening for cystic fibrosis (CF). Adjusting immunoreactive trypsinogen (IRT) cutoffs can improve detection rates and minimize missed cases, enhancing early diagnosis for CF.
Area of Science:
- Biochemistry
- Genetics
- Public Health
Background:
- The California Genetic Disease Screening Program (GDSP) uses a fixed immunoreactive trypsinogen (IRT) cutoff for newborn cystic fibrosis (CF) screening.
- Seasonal variations in IRT levels can affect screening accuracy and lead to missed cases.
Purpose of the Study:
- To develop a model for establishing fixed IRT cutoffs that account for seasonal variations.
- To minimize missed cystic fibrosis cases below the established cutoff.
Main Methods:
- Utilized an ARIMA model to analyze monthly IRT screen-positive percentiles and estimate seasonal expectations.
- Established a retrospective cohort of newborns screened between July 2007 and December 2022.
- Compared missed CF cases identified using seasonal cutoffs versus floating cutoffs.
Main Results:
- A regular seasonal cycle in IRT levels was observed, ranging from 1.4% in summer to 1.8% in winter.
- GDSP screened 7,410,003 newborns and missed 36 CF cases below the fixed cutoff.
- Using a 1.6% daily floating cutoff would have missed 59 CF cases; a 4% daily floating cutoff would be needed to improve detection but double molecular testing.
Conclusions:
- Seasonal variations necessitate adaptive IRT cutoffs in newborn screening for cystic fibrosis.
- Implementing seasonal adjustments can improve the detection rate of CF while managing the number of molecular tests.
Abstract:
The California Genetic Disease Screening Program (GDSP) employs a fixed immunoreactive trypsinogen (IRT) cutoff followed by molecular testing to screen newborns for cystic fibrosis (CF). The cutoffs approximate a 1.6% yearly IRT screen-positive rate; however, seasonal variation in IRT population means has led us to develop a model to establish fixed IRT cutoffs that anticipate seasonal variation and minimize missed cases below cutoff. We utilized an ARIMA model to fit monthly IRT screen-positive percentiles and estimated regular seasonal expectations. We established a retrospective cohort followed for at least 1.5 years to capture missed false-negative CF cases. We compared missed CF cases identified by seasonal cutoffs vs. floating cutoffs. GDSP screened 7,410,003 newborns, from July 2007 to December 2022, and missed 36 CF cases below the fixed cutoff; five of the 36 were within 3 ng/mL below the cutoff. There was a regular, seasonal cycle that varied from 1.4% in summer to 1.8% in winter. We would have missed 59 CF cases using a 1.6% daily floating cutoff. California would need to use a 4% daily floating cutoff to improve our current detection rate, which would double the number of specimens sent for costly molecular analysis.
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