The "Fish that Slipped Through the Net" of Screening: A Study Reveals the Challenges and Optimization Directions of Newborn Screening for Cystic Fibrosis in Turkey
Introduction: The "Protective Net" at the Beginning of Life
The arrival of every new life carries the boundless hopes of a family. To safeguard this hope, modern medicine has established an important line of defense – newborn disease screening. By collecting a few drops of heel blood, doctors can detect some hidden genetic metabolic diseases early, thereby allowing for early intervention to avoid or mitigate the severe consequences of the disease. Cystic Fibrosis (CF) is one such disease. It is a serious genetic disorder that primarily affects the lungs and digestive system, leading to recurrent respiratory infections and malnutrition. Early diagnosis and treatment are crucial for improving the quality of life for affected children. Since 2015, Turkey has implemented a nationwide newborn screening program for CF. However, a recent study published in the "Balkan Medical Journal" evaluated the effectiveness of this program, finding that this 'protective net' has significant loopholes.
Key Findings: Why Does the Screening Net "Miss Fish"?
This retrospective study, conducted by a tertiary pediatric center in the Western Anatolia region of Turkey, revealed several core problems with the current screening program:
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Insufficient Sensitivity, High Missed Diagnosis Rate: The study found that the sensitivity of Turkey's current screening program is only 80.3%. This means that approximately 1 out of every 5 infants with CF is incorrectly told they are "normal" in newborn screening (i.e., false negative), thus missing the optimal window for early diagnosis and intervention. These children are not diagnosed until later when they develop obvious clinical symptoms (such as recurrent pneumonia, growth retardation, etc.), significantly delaying diagnosis.
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High False Positive Rate, Strained Medical Resources: The positive predictive value (PPV) of the screening was only 23.3%. In layman's terms, out of every 100 infants whose screening results were positive and were asked for further examination, only about 23 were ultimately diagnosed with CF. The high false positive rate of over 70% not only caused unnecessary anxiety and panic for countless families but also consumed valuable medical resources for subsequent confirmatory tests such as sweat tests.
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Serious Consequences of Delayed Diagnosis: The study compared children found through screening with those who were missed. The results showed that "false negative" children who were missed had a significantly later age at first visit and diagnosis than children who screened positive. This delay led to them being more prone to severe complications such as malnutrition (developmental delay), prolonged jaundice, and intestinal obstruction. This completely contradicts the core goal of newborn screening: "early detection, early treatment."
Research Methods: Two-Step IRT Testing
Turkey's CF screening uses a "IRT/IRT" two-step method. First, heel blood is collected after the baby's birth to test for a biomarker called "immunoreactive trypsinogen" (IRT). If the first IRT value is high, a second IRT test is performed several weeks later. Only infants with two high test results are determined to be "screen positive" and referred to a CF center for final diagnosis – the sweat chloride test. Abnormally high sweat chloride concentration is the "gold standard" for diagnosing CF. This study drew the above conclusions by retrospectively analyzing data from hundreds of infants referred to the center between 2015 and 2023.
Limitations and Challenges: Where is the Path to Optimization?
The study points out that the current screening program is "impractical" in Turkey. A simple idea is to adjust the "threshold" for IRT testing. Lowering the threshold might catch more "fish that slipped through the net," but this would lead to a surge in false positive rates, putting greater pressure on the healthcare system. Conversely, raising the threshold would exacerbate missed diagnoses.
Another challenge comes from the genetic diversity of the Turkish population. In many countries, a second step of DNA testing is added to screening programs to directly look for known pathogenic gene mutations, which can greatly improve accuracy. However, the types of CF pathogenic gene mutations in the Turkish population are numerous and widely distributed, making it very difficult to design an economical and efficient combination of gene mutation tests. In addition, widespread genetic testing may also discover variants of unknown significance or identify asymptomatic carriers, bringing new ethical and counseling challenges.
Application Prospects: Moving Towards More Precise Screening Strategies
The value of this study lies not only in pointing out problems but also in indicating directions for the future. The researchers emphasize that the optimal IRT threshold suitable for the Turkish population must be re-evaluated and established. More importantly, existing screening strategies need to be revised to reduce false negative cases.
Despite the challenges, integrating DNA analysis (such as Next-Generation Sequencing technology) into the screening process is key to improving screening efficiency. By identifying a wider range of genetic variants, especially mutations specific to different ethnic groups, the sensitivity and specificity of screening can be significantly improved. The study also suggests that clinical diagnosis should not rely solely on genotype and laboratory data; for infants with typical clinical symptoms but unclear genetic test results, diagnosis and management should also be based on clinical manifestations.
Summary
Newborn screening is a great public health initiative, but it is not a one-time fix. This study from Turkey clearly shows that any screening program needs to be continuously evaluated, reflected upon, and optimized in practice. A seemingly standard screening program may not be effective in a specific population. To truly protect every new life, we need to adapt to local conditions and develop more precise and efficient screening strategies to ensure that no "fish" slips through the protective net.
