Changes of <scp>CEA</scp> Diagnostic Performance Under the New Reference Interval Stratified by Age and Sex

BACKGROUND: CEA is one of the most frequently used biomarkers for cancer, but its inappropriate reference interval, low sensitivity, and specificity limit its clinical application. METHODS: We retrospectively analyzed carcinoembryonic antigen levels in 49,752 apparently healthy Chinese individuals (23,967 men vs. 25,785 women), 9830 patients with lung cancer (4493 men vs. 5337 women), 5104 women with breast cancer, and 4154 patients with colorectal cancer (2590 men vs. 1564 women) to investigate effects of age and sex on CEA levels, as well as to analyze the changes in CEA diagnostic performance for three common cancers under the new reference interval. RESULTS: The concentration distribution of CEA in apparently healthy populations was associated with both sex and age. The positive rates of CEA for apparently healthy Chinese males and females were 6.49% and 1.26%. The positive rates of CEA among patients with breast cancer, lung cancer, and colorectal cancer were 8.19%, 21.55%, and 26.62%, respectively. According to the updated reference interval, the sensitivity and Youden index increased, while specificity, positive predictive value, and positive likelihood ratio decreased in male patients < 40 years and female cases < 70 years. Conversely, sensitivity and Youden index decreased, while specificity, positive predictive value, and positive likelihood ratio increased in male patients ≥ 50 years and female cases ≥ 70 years. CONCLUSIONS: The concentration distribution of CEA in apparently healthy populations is associated with sex and age. Although adjusting to a lower threshold may enhance sensitivity, it can lead to the misclassification of numerous non-cancer cases. IMPACT STATEMENT: In the era of precision medicine, tumor markers have become increasingly important given that their results may be critical determinants in the decision to proceed with or withhold effective therapies that may have substantial toxicities; they also play an important role in the risk assessment and prognosis model of cancer. The main disadvantages of existing serum markers are lack of sensitivity and specificity. In addition, inappropriate reference intervals can profoundly influence the clinical application of tumor markers. Our study included patients with lung cancer, breast cancer, and colorectal cancer and apparently healthy individuals, and conducted a large case-control study to assess the effects of age and sex on serum concentrations and positive rates of CEA, establishing age- and sex-stratified reference intervals using indirect methods. We also analyzed the alterations in the diagnostic performance of CEA in the three prevalent cancers under the new and old reference intervals.