br Discussion This approach is in line with the recommendati

Discussion This approach is in line with the recommendations of the Institute of Medicine [23] and the General Medical Council of the UK [24], who promote informed decision making by informing prospective screening participants of their individual risk and allowing them to choose a screening test accordingly [25]. People should have the opportunity to be informed about their individual risk of pre-cancerous lesion and CRC detection. Several institutions advocate for clear communication and recommendation from the GPs to participants [23,24,26,27]. Informed decision making is most likely associated with higher participation rates and compliance [28]. It should be clear that everyone with FIT ≥75 ng/ml is advised to undergo a subsequent colonoscopy, while their individual risks differ considerably. This study reported on the association between gender, age and quantitative FIT results and the detection of pre-cancerous lesions, CIS and CRC in non-symptomatic participants in the Flemish CRC screening programme which is consistent with other studies [11,29]. However, the large sample size of 57,421 participants leads to a more precise risk Gilteritinib compared to other studies. This study views the question of possible quality improvement of the screening programme within the positively screened group where ∼27% undergo a negative colonoscopy. The screening process needs to be improved to reduce the number of negative colonoscopies after a positive FIT. These are an unnecessary burden for the participants and are expensive in these large numbers (approximately €4.74 million per year for colonoscopies with no anomalies) [30]. Considering that negative colonoscopies occur over the whole range of FIT, adapting the FIT cut-off value per subgroup (e.g., increase cut-off in younger women or lower cut-off in older-men) would only shift the problem. Changing the FIT cut-off based on gender through multiple options could bring the differences between gender closer together in terms of accuracy or miss rates [31]. Increasing the FIT cut-off for women could lead to similar miss rates and positive predictive values between genders, but would decrease sensitivity and detection rates in females. Several of these considered options have their benefits and disadvantages. Nevertheless, the goal should be to reduce the negative colonoscopies and maintain the detection of pre-cancerous lesions and CRC. A more promising approach could therefore be a personalized screening follow-up, based on a prediction model. Additional predictors, accompanied by the quantitative FIT, could make a more accurate prediction between participants with or without neoplasia. Natural considerations are gender and age but also other easily obtainable risk factors such as smoking, alcohol use, BMI, family history of CRC etc. In addition, we should also consider molecular and genetic markers, through molecular pathological epidemiology (MPE) for improving the early detection of CRC [32]. This brings the screening from a binary approach to an approach where probabilities are considered. It would be the most favourable approach for attaining fewer false positive colonoscopies and retaining the detection of pre-cancerous lesions, CIS and CRC. Comparable results were found in a German study where the male gender and increasing FIT results were associated with an increased risk of detecting CRC (OR 1.9 and 2.4, respectively) while increasing age showed inconsistent results [33]. A Spanish study showed that increased risk of CRC was found based on the risk factors gender (male OR 2.07), age (60–69 OR 1.24) and FIT ng/ml (165–320, 325–885 and >885 OR 1.23, 2.00 and 3.80, respectively) [11]. This latter study developed a risk matrix of 16 risk categories, where vacuoles found an (OR 11.46 fold) increase between risk categories [11]. Unfortunately, pre-cancerous lesions were not considered in these studies and this is an essential part of the screening programme. These European studies show less specific, but similar results compared to this study in terms of risk factors for CRC detection.