ABSTRACT
Colorectal cancer (CRC) screening reduces disease burden, but the comparative performance of various screening strategies remains unclear. We evaluated the performance of four screening strategies based on questionnaire‐based risk assessment (QRA) and fecal immunochemical test (FIT), followed by colonoscopy. In this population‐based study, 14,327 residents aged 40–74 years from 13 regions in Shandong Province, China, were invited to undergo QRA, FIT, and colonoscopy between January 2024 and December 2025. Based on test results, we constructed four strategies: QRA‐only, FIT‐only, parallel (QRA or FIT positive), and tandem (QRA and FIT positive) combinations. The detection rate of CRC and advanced adenoma (AA), number needed to scope (NNS), and cost per case detected were compared. In total, 4982, 1806, 5970, and 764 individuals were identified as high‐risk for each strategy. The tandem strategy detected 33 CRCs (4.32%) and 199 AAs (26.03%), compared with 35 (0.71%) and 553 (11.22%) in the QRA‐only strategy, 68 (3.77%) and 340 (18.86%) in the FIT‐only strategy, and 70 (1.17%) and 694 (11.62%) in the parallel strategy. Across subgroups defined by older age, male, and early‐stage disease, the tandem strategy consistently yielded higher detection rates. The NNS to detect one CRC was 141, 27, 86, and 24, and the corresponding costs per CRC detected were $9874.31, $2097.88, $7084.68, and $1700.71 for each strategy. The tandem strategy combining QRA and FIT demonstrated superior performance in CRC screening. In resource‐constrained settings, tandem strategies that jointly integrate risk assessment and FIT may improve the allocation and utilization of screening resources.
Keywords: colonoscopy, colorectal cancer screening, fecal immunochemical test, risk stratification, screening strategies
What's New?
Colorectal cancer screening reduces disease burden, but the comparative performance of screening strategies remains unclear. This population‐based study shows that the tandem strategy (positive results from both questionnaire‐based risk assessment and fecal immunochemical testing) substantially improved the detection rates of colorectal cancer and advanced adenomas compared with questionnaire‐based risk assessment only, fecal immunochemical testing only, and the parallel strategy (positive results from either questionnaire‐based risk assessment or fecal immunochemical testing). The tandem strategy also reduced the colonoscopy number and the cost per detected cancer. This study supports the tandem combination as a feasible and cost‐benefit strategy for colorectal cancer screening.
Colorectal cancer screening reduces disease burden, but the comparative performance of screening strategies remains unclear. This population‐based study shows that the tandem strategy (positive results from both questionnaire‐based risk assessment and fecal immunochemical testing) substantially improved the detection rates of colorectal cancer and advanced adenomas compared with questionnaire‐based risk assessment only, fecal immunochemical testing only, and the parallel strategy (positive results from either questionnaire‐based risk assessment or fecal immunochemical testing). The tandem strategy also reduced the colonoscopy number and the cost per detected cancer. This study supports the tandem combination as a feasible and cost‐benefit strategy for colorectal cancer screening.
Abbreviations
- AA
advanced adenoma
- APCS
Asia‐Pacific Colorectal Screening score
- BMI
body mass index
- CIs
confidence intervals
- CNY
Chinese Yuan
- CRC
colorectal cancer
- FIT
fecal immunochemical test
- ICD‐10
International Classification of Diseases, 10th Revision
- NAA
non‐advanced adenoma
- NNS
number needed to scope
- ORs
odds ratios
- QRA
questionnaire‐based risk assessment
- RCT
randomized controlled trial
- RF‐FIT
risk factor–fecal immunochemical test
- US
United States
- WHO
World Health Organization
1. Introduction
Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer‐related deaths, posing a significant threat to human health. In 2022, approximately 27% of new cases and 30.6% of CRC‐related deaths occurred in China [1]. Screening can reduce CRC burden by enabling the early detection of lesions [2, 3]. Colonoscopy is considered to be the gold standard for CRC screening [4], but it has several drawbacks including unsatisfactory participation, low yield for neoplasia, and high demand for endoscopy resources. To address these issues, the preliminary identification of high‐CRC‐risk individuals in the general population, based on CRC risk assessments, could improve CRC screening efficiency.
Among the well‐established CRC risk‐stratified screening modalities, questionnaire‐based risk assessment (QRA) and fecal immunochemical testing (FIT) are the most widely used tools and have been widely adopted in nationwide CRC screening programs [5, 6]. Previous studies have demonstrated that those two approaches can further identify high‐risk populations, thereby improving the detection rates of cases [7, 8]. A recent randomized controlled trial (RCT) indicated that the risk‐adapted approach is a feasible and cost‐favorable strategy compared with the Colonoscopy‐only strategy [9]. Combining the risk questionnaire with FIT positive results offers a greater detection rate than screening with FIT alone [10]. The China Urban Cancer Screening Project also showed that combining QRA with FIT could enhance the detection rate of CRC [11]. However, the evidence of such a combined strategy, where both the QRA and FIT are positive or either one is positive, remains sparse and needs further validation to inform its clinical application.
From January 1, 2024 to December 31, 2025, residents aged 40–74 years old from 13 regions were invited to undergo risk questionnaire assessment, FIT testing, and colonoscopy. We compared the tandem strategy combining co‐positive results of QRA and FIT with the parallel strategy combining either positive results of QRA or FIT, the QRA‐only strategy, and the FIT‐only strategy to evaluate differences in screening yield, colonoscopy burden, and cost benefit for CRC screening.
2. Materials and Methods
2.1. Study Design and Study Population
This study was conducted within an organized, population‐based CRC screening program implemented in 13 regions of Shandong Province, China. Eligible residents aged 40–74 years were recruited by trained staff in selected communities and assessed for eligibility. Individuals meeting any of the following criteria were excluded: (1) diagnosis of cancer; (2) history of colonic resection; (3) previously diagnosed as high‐risk for CRC; (4) presence of other major diseases, such as severe cardiovascular disease or advanced renal dysfunction; (5) lack of independent mobility.
2.2. Screening Workflow
Participants underwent a structured screening process. All eligible individuals completed the QRA and FIT. Based on the results of the QRA and FIT, participants were stratified into different screening strategies. Individuals identified as high‐risk under each strategy were referred for colonoscopy. Based on the results of the QRA and FIT, four screening strategies were established (Figure 1): (1) QRA‐only strategy: participants were evaluated by using the QRA, and those identified as high risk were referred for colonoscopy; (2) FIT‐only strategy: after evaluating FIT, positive ones were referred for colonoscopy; (3) parallel strategy: colonoscopy was referred to the participants with QRA or FIT positive results; (4) tandem strategy: only participants with positive results on both QRA and FIT were referred for colonoscopy.
FIGURE 1.
Study design and flowchart. FIT, fecal immunochemical test; QRA, questionnaire‐based risk assessment.
2.3. Screening Procedure
2.3.1. Questionnaire‐Based Risk Assessment Procedure
This study used a modified version of the Asia‐Pacific Colorectal Screening risk assessment questionnaire, incorporating the following risk factors: (1) demographic characteristics: gender (0: female; 1: male), age (0: 40–54 years; 1: 55–64 years; 65–70 years), first‐degree relative history of CRC (0: none; 1: present); (2) lifestyle factors: smoking history (0: none; 1: present), BMI (0: < 23 kg/m2; 1: ≥ 23 kg/m2). The risk score for each participant was calculated as the total of their individual risk factors, with a score of ≥ 3 indicating high risk for CRC [12, 13, 14].
2.3.2. FIT Procedure
A quantitative FIT (version, FUNUOTEC) was used by following the standard operating procedure. While mainstream studies typically use 10 μg Hb/g (10 μg Hb/g = 50 ng/mL) as the positive threshold [15]. Previous research indicates that certain populations, such as women and the elderly, may benefit from personalized adjustments to the FIT threshold. Therefore, this study uses FIT (positive threshold of 10 ng/mL) to detect human hemoglobin concentration in fecal samples to enhance screening sensitivity and improve the early detection rate of CRC [16]. Given that factors such as hemorrhoidal bleeding, menstruation, non‐steroidal anti‐inflammatory drug use (e.g., aspirin), gum bleeding, and gastrointestinal ulcers may affect the accuracy of FIT results, participants with these conditions were advised to delay sampling or retake fecal samples to ensure the objectivity and reliability of the test results.
2.3.3. Colonoscopy Procedure
Colonoscopy will be performed by experienced endoscopists, with all procedures conducted following standardized clinical protocols. Any lesions detected during the colonoscopy will undergo biopsy, and the pathological results will serve as the definitive diagnosis. The endoscopists will record the colonoscopy findings in the system, including the lesion's location, position, suspected lesion type, maximum diameter, shape, and other relevant details. For biopsied lesions, experienced pathologists will evaluate them based on the pathological type.
2.4. Outcomes
The primary outcome was detection rate of CRC, AA, and NAA. Secondary outcomes included NNS and the cost per case detected. Final clinical diagnoses were classified according to the findings reported in histology reports. CRC was defined as adenocarcinoma of the colon or rectum. The International Classification of Diseases,10th Revision (ICD‐10) codes were used throughout, in which CRC was coded as C18–C21. Advanced adenomas included (1) adenomas with a diameter ≥ 1 cm; (2) tubular villous adenomas; (3) serrated adenomas; and (4) high‐grade intraepithelial neoplasia [17]. Non‐advanced adenomas included a diameter < 1 cm, predominantly tubular structure (with villous component < 25%) and without moderate or severe atypical hyperplasia [18].
2.5. Statistical Analysis
The overall demographic characteristics were calculated using proportions, and the distribution characteristics of high‐risk populations identified by four screening strategies were compared using chi‐squared test or Fisher's exact test. Quantitative variables in this study, such as age, have been grouped by referencing relevant literature and presented in the results. The detection rates of lesions (NAAs, AAs, and CRCs), number of cases detected per thousand individuals, and corresponding colonoscopy burden were calculated as follows:
Specificity was defined as the proportion of individuals without colorectal neoplasms who were correctly identified as negative. Positive predictive value (PPV) and negative predictive value (NPV) were calculated as the proportion of true positive and true negative results among all positive and negative test results, respectively.
Cost analysis was conducted from a societal perspective, the per‐participant direct cost and indirect cost in this study were calculated using multiple approaches, including the field interview with the management staff, micro‐costing, and human capital approach. The direct costs (including direct medical costs, direct non‐medical costs) were calculated using a micro‐costing approach based on an estimated cost‐to‐price ratio of approximately 0.76. Indirect costs were assessed using the human capital method, incorporating comprehensive estimates of per capita disposable income and an employment rate of approximately 0.85, based on data from 2024.1.1 to 2025.5.30 [19]. All costs were initially recorded in CNY and subsequently converted to US$ dollars at an exchange rate of 1 US$ = 7.2 CNY (based on the 2024 annual average rate). To assess the robustness of the findings, one‐way sensitivity analyses were conducted to examine the impact of variations in the unit costs of risk questionnaire, FIT, and colonoscopy.
To account for potential confounding factors, multivariable regression analyses were performed to evaluate the association between different screening strategies and outcomes (CRC and AA). Logistic regression models were constructed with detection outcomes as dependent variables and screening strategy as the main independent variable. Covariates included age, sex, smoking status, body mass index (BMI), and family history of CRC. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.
All statistical tests in this study were two‐sided, with a significance level set at α = 0.05, and results with p < 0.05 were considered statistically significant. All analyses were conducted in R.4.3.2 software.
3. Results
3.1. Study Population Characteristics
14,327 individuals were enrolled in the study (Figure 2). After excluding those with incomplete risk questionnaire, invalid FIT and those not classified as high risk, 4928 high‐risk participants were included in the risk questionnaire strategy and 1806 high‐risk individuals were included in the FIT strategy. Among those who were tested as positive, 5970 individuals with a positive result on either the risk questionnaire or FIT were included in the parallel strategy, and 764 participants with co‐positive results on the risk questionnaire and FIT were included in the tandem strategy. The characteristics of the study population are shown in Table 1. Of the 14,327 participants, the mean age was 56.96 ± 0.07 years. Approximately 55.2% of the participants were female, 34.2% were overweight, 81.6% had a history of smoking, and 66.1% reported alcohol use. Only 4.6% reported a family history of CRC. The baseline characteristics were comparable between the four strategies (p < 0.001).
FIGURE 2.
Schematic illustration of screening strategies. AA, advanced adenoma; CRC, colorectal cancer; FIT, fecal immunochemical test; NAA, non‐advanced adenoma.
TABLE 1.
Characteristics of the overall population and high‐CRC‐risk individuals identified using risk questionnaire, FIT, parallel, and tandem strategies.
| Characteristics | Overall (n = 14,327) | QRA‐only strategy (n = 4928) | FIT‐only strategy (n = 1806) | Parallel strategy a (n = 5970) | Tandem strategy b (n = 764) | χ 2 | p |
|---|---|---|---|---|---|---|---|
| Gender | 350.15 | < 0.001 | |||||
| Female | 7903 (55.16) | 1263 (25.63) | 856 (47.40) | 1972 (33.03) | 147 (19.24) | ||
| Male | 6424 (44.84) | 3665 (74.37) | 950 (52.60) | 3998 (66.97) | 617 (80.76) | ||
| Age | 809.02 | < 0.001 | |||||
| 40–54 | 5350 (37.34) | 336 (6.82) | 540 (29.90) | 841 (14.09) | 35 (4.59) | ||
| 55–64 | 5668 (39.56) | 1838 (37.30) | 751 (41.58) | 2289 (38.34) | 300 (39.27) | ||
| 65–74 | 3309 (23.10) | 2754 (55.88) | 515 (28.52) | 2840 (47.57) | 429 (56.15) | ||
| BMI (kg/m2) | 55.62 | < 0.001 | |||||
| < 18.5 | 2641 (18.43) | 680 (13.80) | 340 (18.83) | 910 (15.24) | 110 (14.40) | ||
| 18.5–24.9 | 6781 (47.33) | 2114 (42.89) | 851 (47.12) | 2630 (44.05) | 335 (43.85) | ||
| > 24.9 | 4905 (34.24) | 2134 (43.31) | 615 (34.05) | 2430 (40.71) | 319 (41.75) | ||
| Smoking history | 202.69 | < 0.001 | |||||
| No | 11,687 (81.57) | 2885 (58.55) | 1336 (73.86) | 3846 (64.47) | 375 (49.08) | ||
| Yes | 2640 (18.43) | 2043 (41.45) | 470 (26.14) | 2124 (35.58) | 389 (50.92) | ||
| Alcohol history | 87.18 | < 0.001 | |||||
| No | 9463 (66.05) | 2494 (50.60) | 1092 (60.47) | 4144 (69.41) | 327 (42.80) | ||
| Yes | 4864 (33.95) | 2434 (49.40) | 714 (39.53) | 3517 (58.91) | 437 (57.20) | ||
| Family history of CRC c | 2820 | < 0.001 | |||||
| No | 13,664 (95.37) | 4531 (91.94) | 1750 (96.90) | 3259 (54.59) | 726 (95.03) | ||
| Yes | 663 (4.63) | 397 (8.06) | 56 (3.10) | 2711 (45.41) | 38 (4.97) | ||
| Annual household income | 57.34 | < 0.001 | |||||
| < 20,000 | 2601 (18.15) | 1182 (23.98) | 435 (24.09) | 1375 (23.03) | 242 (31.68) | ||
| 20,000–59,999 | 4829 (33.71) | 1873 (38.01) | 737 (40.81) | 2302 (38.56) | 308 (40.31) | ||
| 60,000–99,999 | 3779 (26.38) | 1149 (23.31) | 415 (22.98) | 1410 (23.62) | 154 (20.16) | ||
| ≥ 100,000 | 3118 (21.76) | 724 (14.69) | 219 (12.13) | 883 (14.79) | 60 (7.85) | ||
Abbreviation: CRC, colorectal cancer.
Parallel strategy: either the risk questionnaire or the FIT is positive.
Tandem strategy: both the risk questionnaire and FIT are positive.
Family history of CRC: family history of colorectal cancer in first‐degree relatives. BMI (Body Mass Index) was categorized based on WHO recommendations as underweight (< 18.5 kg/m2), normal (18.5–24.9 kg/m2), and overweight/obese (> 24.9 kg/m2).
3.2. Detection Rates and Colonoscopy Burden of Various Screening Strategies
Table 2 presents the screening yield of the four screening strategies. Advanced neoplasm detection rates in the tandem strategy were significantly higher than the other three strategies. Specifically, 33 (4.32%, 95% CI: 3.01%–5.25%) CRCs and 199 (26.03%, 95% CI: 22.92%–29.24%) AAs were detected in the tandem strategy, which was significantly higher than in the QRA‐only strategy [CRCs: 35 (0.71%, 95% CI: 00.50%–0.90%); AAs: 553 (11.22%, 95% CI: 10.31%–12.13%)], FIT‐only strategy [CRCs: 68 (3.77%, 95% CI: 2.89%–4.65%); AAs: 340 (18.86%, 95% CI: 17.05%–20.66%)], and parallel strategy [CRCs: 70 (1.17%, 95% CI: 0.90%–1.44%); AAs: 694 (11.62%, 95% CI: 10.79%–12.45%)]. However, the tandem strategy did not demonstrate a substantial advantage in NAA detection. Multivariable logistic regression analyses adjusting for age, gender, smoking status, BMI, and family history of CRC showed that the associations between the four screening strategies and CRC and AA detection remained statistically significant and largely unchanged, indicating robustness of the findings. The detailed results of covariates are provided in Tables S1 and S2. Also, the tandem strategy demonstrated the highest PPV and specificity for both CRC and AA, indicating a substantial reduction in false‐positive results (see Table S3).
TABLE 2.
Detection rate and colonoscopy burden of colorectal neoplasms in different screening scenarios.
| Outcomes | QRA‐only strategy (n = 4928) | FIT‐only strategy (n = 1806) | Parallel strategy a (n = 5970) | Tandem strategy b (n = 764) | χ 2 | p | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| Detected cases | Rate [% (95% CI)] | Detected cases | Rate [% (95% CI)] | Detected cases | Rate [% (95% CI)] | Detected cases | Rate [% (95% CI)] | |||
| Advanced neoplasm | 58 | 11.93 (11.00, 12.85) | 408 | 22.63 (20.71, 24.56) | 764 | 12.80 (11.94, 13.65) | 232/764 | 30.37 (27.12, 33.65) | 285.05 | < 0.001 |
| CRC | 35 | 0.71 (0.48, 0.93) | 68 | 3.77 (2.89, 4.65) | 70 | 1.17 (0.90, 1.44) | 33/764 | 4.32 (2.88, 5.75) | 126.43 | < 0.001 |
| Advanced adenoma | 553 | 11.22 (10.31, 12.13) | 340 | 18.86 (17.05, 20.66) | 694 | 11.62 (10.79, 12.45) | 199/764 | 26.03 (22.92, 29.24) | 188.93 | < 0.001 |
| Non‐advanced lesions | 2207 | 44.80 (43.33, 46.28) | 742 | 41.15 (38.88, 43.43) | 2603 | 43.59 (42.23, 44.95) | 346/764 | 45.29 (41.64, 48.94) | 8.14 | 0.043 |
| Non‐advanced adenoma | 1600 | 32.47 (31.06, 33.87) | 571 | 31.67 (29.52, 33.82) | 1881 | 31.51 (30.26, 32.76) | 290/764 | 37.98 (34.44, 41.62) | 13.34 | 0.004 |
| Other benign lesions | 607 | 12.32 (11.37, 13.27) | 171 | 9.48 (8.13, 10.84) | 722 | 12.09 (11.24, 12.95) | 56/764 | 7.33 (5.54, 9.11) | 25.54 | < 0.001 |
Abbreviations: CRC, colorectal cancer; FIT, fecal immunochemical test; QRA, questionnaire‐based risk assessment.
Parallel strategy: either the risk questionnaire or the FIT is positive.
Tandem strategy: both the risk questionnaire and FIT are positive.
Regarding the number of colonoscopies needed to detect one advanced neoplasm, the tandem strategy was the most efficient compared with the other three strategies, with 9 (95% CI, 7.86–9.10), 5 (95% CI, 4.08–5.01), 8 (95% CI, 7.22–8.41), and 4 (95% CI, 2.88–4.11) colonoscopies required for the QRA‐only strategy, FIT‐only strategy, parallel strategy, and tandem strategy, respectively (Table 3).
TABLE 3.
Number of colonoscopies needed to be performed to detect one lesion for different screening scenarios.
| Screening scenarios | Number of colonoscopies needed to be performed to detect [n (95% CI)] | |||
|---|---|---|---|---|
| One advanced neoplasm | One colorectal cancer | One advanced adenoma | One non‐advanced adenoma | |
| QRA‐only strategy | 9 (7.86–9.10) | 141 (100.75–233.21) | 9 (8.04–9.76) | 4 (3.11–4.26) |
| FIT‐only strategy | 5 (4.08–5.01) | 27 (19.21–35.21) | 6 (5.20–6.85) | 4 (3.20–4.56) |
| Parallel strategy | 8 (7.22–8.41) | 86 (65.33–111.56) | 9 (7.96–8.95) | 4 (2.96–4.82) |
| Tandem strategy | 4 (2.88–4.11) | 24 (16.01–32.72) | 4 (3.11–4.95) | 3 (1.96–3.98) |
Abbreviations: 95% CI, 95% confidence interval; FIT, fecal immunochemical test; QRA, questionnaire‐based risk assessment.
Detection rates for advanced neoplasms increased with age in both groups (Figure 3). The overall trend for detection rates in the tandem strategy was higher than that in the other strategies, with similar trends in both men and women (p < 0.001). The percentage of stage I‐II CRC in the tandem strategy was much higher than that in the other three strategies (3.22%, vs. 0.64%, 0.5%, and 2.15%, p = 0.016). The detection rate of early‐stage CRC is presented in Figure S1.
FIGURE 3.
Detection rates stratified by gender and age across the four screening strategies: QRA‐only strategy, FIT‐only strategy, parallel strategy, and tandem strategy.
3.3. Costing Outcomes
From a social perspective, the cost was $4.08 for questionnaire risk assessment, $12.94 for FIT, and $66.05 for colonoscopy (see Table S4). The cost per participant, per CRC and AA case detected by the tandem strategy was $1700.71 and $282.03, respectively, both of which were lower than those observed with the other three strategies (see Tables S5 and S6).
One‐way sensitivity analyses further indicated that the superiority of the tandem strategy in detecting CRC remained consistent, even when the aggregated costs of QRA and FIT were varied across plausible ranges, supporting the robustness of the findings. The detailed information is shown in Figure S2.
4. Discussion
This study showed that the tandem combination of QRA and FIT is a feasible and cost–benefit strategy. To our knowledge, this is the first study to comparatively evaluate the screening yield and economic viability of various screening strategies combining QRA and FIT in the CRC screening program. The large sample size and the use of colonoscopy in all eligible positive individuals make the study unique.
Identifying high‐risk individuals is a crucial step in CRC screening, especially in resource‐limited countries. A recent study has shown that pre‐identifying high‐risk populations, followed by colonoscopy, can significantly improve screening efficacy and reduce resource waste [20]. The QRA and FIT are the most widely used tools and have been widely adopted in nationwide CRC screening programs [5, 6]. Previous studies have demonstrated that those two approaches can further identify high‐risk populations, thereby improving the detection rates of cases [8, 21]. Several studies have confirmed that the APCS‐based risk stratification strategy is effective in identifying high‐risk CRC populations, offering advantages such as ease of data acquisition, simplicity in operation, and low implementation costs. However, risk assessment tools still have certain limitations in diagnostic efficacy [22, 23]. When used independently, these tools still had insufficient ability to identify advanced lesion [24].
A recent RCT study indicated that the risk‐adapted approach is a feasible and cost‐favorable strategy compared with colonoscopy‐only strategy [9]. Combining risk questionnaire with FIT positive results offers a greater detection rate than screening with FIT alone [8]. The China Urban Cancer Screening Project also showed that combining questionnaire‐based risk assessments with FIT could enhance the detection rate of CRC [11]. However, the evidence of such a combined strategy, where both the risk questionnaire and FIT are positive or either one is positive, remains sparse and needs further validation to inform its clinical application. In this study, we conducted a population‐based study to evaluate the screening yield and economics of the tandem and parallel combination of the risk questionnaire and FIT, risk questionnaire‐only strategy, and FIT‐only strategy.
Detection rate is the critical indicator to confirm the efficiency of those strategies. This study found that the tandem combination of the risk questionnaire and FIT achieved the highest detection rate, identifying 33 (4.59%) CRCs and 199 (26.03%) AAs. This is consistent with previous studies, which reported that the Risk factor–fecal immunochemical test (RF–FIT) strategy improves the detection of CRC and AA [11]. However, a study conducted in China found that the parallel combination of questionnaire and FIT did not show superior efficacy for detecting advanced neoplasm compared with FIT alone. Our study also found that, across different age groups, the overall trend in detection rates with the tandem strategy was higher than that observed with the risk questionnaire–only, FIT‐only, and parallel strategies, with similar patterns in both men and women (p < 0.001). Similarly, previous studies have demonstrated that the combined risk questionnaire and FIT strategy yields higher detection rates across sex and age subgroups compared with single screening strategies [24, 25]. In particular, individuals over 50 years of age have significantly higher CRC detection rates than younger populations, with the detection rates of AA and CRC in the 70–75‐year age group being significantly higher than those in the 50–54‐year age group [26]. In addition, men are known to have a higher risk of CRC, with consistently higher detection rates reported in this group [27]. We also found that the percentage of stage I‐II CRC in the tandem strategy was much higher than that in the risk questionnaire strategy, FIT strategy, and parallel strategy (3.22%, vs. 0.64%, 0.5%, and 2.15%, p = 0.016). Similarly, Dong et al. [11] reported that the proportion of stage I–II CRC in the RF–FIT group was much higher than that in the RF group. Overall, the tandem strategy demonstrated excellent detection performance not only in the total population but also across subgroups stratified by sex, age, and family history. Importantly, after adjustment for potential confounders (including age, sex, smoking, BMI, and family history), the superiority of the tandem strategy remained largely unchanged, supporting the robustness of the findings.
Although the tandem strategy identified more CRCs and AAs, this advantage needs to be considered alongside its practical implementation in real‐world settings. Participation is a critical determinant of screening effectiveness at the population level [7]. Questionnaire‐based risk assessment is generally well accepted due to its non‐invasive nature, whereas strategies requiring combined testing may potentially reduce participation because of increased complexity. On the other hand, an important finding of this study is that the tandem strategy required the lowest number of colonoscopies per detected case, indicating a lower colonoscopy burden compared with other strategies. This suggests that, despite involving combined testing, the tandem approach may represent a more efficient use of limited endoscopic resources. The overall value of a screening strategy should be evaluated by balancing detection yield, participation, and resource utilization. In settings with constrained colonoscopy capacity, the tandem strategy may offer a favorable trade‐off between effectiveness and efficiency.
The needs of endoscopy required to detect one lesion is also a key factor that must be considered when formulating screening strategies. A recent study reported the overuse of colonoscopy in the United States Department of Veterans Affairs health system [28]. More than 24% of colonoscopies were suspected to be overused, which was in line with the results from a recent study in the USA [29]. China is confronted with the opposite challenge due to its large population base and limited colonoscopy resources. In this context, many studies have explored the colonoscopy burden associated with different screening strategies. Dong et al. [11] reported that, compared with the RF strategy, the RF–FIT strategy required far fewer colonoscopies to detect one CRC (191 vs. 625) and one advanced adenoma (10 vs. 16), and achieved a higher screening yield per 10,000 invitees for both CRC (15 vs. 4) and advanced adenoma (289 vs. 127). Chen et al. [7] showed that adding a questionnaire to FIT increased the detection of advanced adenomas and other benign lesions but required many more colonoscopies (969 additional) compared with FIT alone. In our study, the tandem strategy was the most efficient compared with the other three strategies, with 9, 5, 8, and 4 colonoscopies required for the risk questionnaire strategy, FIT strategy, parallel strategy, and tandem strategy, respectively. In addition to colonoscopy burden, specificity is another critical parameter when evaluating screening strategies, as it directly reflects the likelihood of false‐positive findings and unnecessary follow‐up procedures [20]. In our study, the tandem strategy demonstrated improved specificity compared with the other strategies, indicating a more efficient selection of high‐risk individuals and a reduction in avoidable colonoscopies. This was further supported by its higher PPV, suggesting that individuals with positive results were more likely to truly have disease. Therefore, balancing detection rates, colonoscopy burden, and specificity is essential when optimizing CRC screening strategies, particularly in resource‐limited settings.
The cost is always one of the key considerations in screening programs. In a study conducted in Nigeria, the cost per detected case of CRC using the FIT screening strategy, followed by colonoscopy for positive individuals, was $43,591 [30]. This is substantially higher than the cost of the FIT strategy in our study ($2097.88), which may be attributable to differences in healthcare systems, unit prices of tests and procedures, and overall resource availability. Additionally, our research also provides data on the screening costs of the tandem combination of questionnaire and FIT, which shows that the cost ($1700.71) is lower compared to single screening strategies and the parallel strategy. For developing countries with limited resources but an increasing CRC burden, cost‐effective screening strategies are particularly crucial. It deserves to be noted that the per‐person cost may vary greatly in different settings. We further conducted a sensitivity analysis varying the costs of questionnaire, FIT, and colonoscopy at a widely acceptable range.
5. Limitation
This study has several limitations. First, the compliance rate with colonoscopy among participants who tested positive (either by FIT or questionnaire) was not considered, which may lead to an overestimation of real‐world effectiveness. However, this assumption provides greater statistical power for evaluating and comparing the performance of different screening strategies. Second, we did not evaluate the long‐term CRC mortality in the four screening strategies. Although surrogate outcomes such as detection rates of CRC and AA were used, they may not fully capture the long‐term effectiveness of each strategy. Nevertheless, a long‐term evaluation is currently underway, and follow‐up of health outcomes through linkage with national cancer registry data and death certificates will be conducted in future analyses. Third, considering the high demand for endoscopists and the regional disparities in medical technology within the screening program, we did not establish unified parameters for endoscopists regarding intubation rates and the detection rates of different lesions. However, at the outset of inclusion, individual endoscopists in four groups were in full agreement, which helped mitigate potential bias.
6. Conclusion
This study demonstrated that the tandem combination of the QRA with FIT is a feasible and cost–benefit strategy. Those findings could be adopted as a promising strategy in future population‐based CRC screening programs, especially in constrained healthcare resource settings, as it maximizes screening benefits and optimizes resource allocation.
Author Contributions
Ruyue Liu: conceptualization, data curation, writing – original draft, validation, methodology, investigation, software. Junyi Ji: validation, writing – original draft, investigation, software. Xiaolin Wei: formal analysis, validation, writing – review and editing. Chao Zheng: data curation, validation, writing – review and editing. Nan Zhang: funding acquisition, supervision, writing – review and editing, validation, conceptualization, resources. Qiang Sun: writing – review and editing, conceptualization, supervision, project administration, validation, visualization.
Funding
This study was funded by the National Natural Science Foundation of China (grant number 72574131) and the Collaborative Academic Innovation Project of Shandong Cancer Hospital (TS001).
Ethics Statement
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of Shandong University (No. LL20240353), and Shandong Cancer Hospital and Institute (No. SDTHEC2024003167). Eligible patients were enrolled in the study and provided written informed consent.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Table S1: Adjusted detection rates and odds ratios for CRC and AA according to screening strategy.
Table S2: Impact of concomitant variables on the detection of CRC and AA across different screening strategies.
Table S3: Positive predictive value, negative predictive value and specificity of CRC and AA in different screening scenarios.
Table S4: The average cost of QRA, FIT, colonoscopy.
Table S5: The aggregated costs for each participant.
Table S6: Average Screening cost of difference strategies.
Figure S1: Detection rates of stage I–IV across the four screening strategies.
Figure S2: One‐way sensitivity analysis.
Acknowledgments
The authors wish to thank all of the participants and graduate students who participated in the field survey.
Contributor Information
Nan Zhang, Email: nanzhang@sdfmu.edu.cn.
Qiang Sun, Email: qiangs@sdu.edu.cn.
Data Availability Statement
All data are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Adjusted detection rates and odds ratios for CRC and AA according to screening strategy.
Table S2: Impact of concomitant variables on the detection of CRC and AA across different screening strategies.
Table S3: Positive predictive value, negative predictive value and specificity of CRC and AA in different screening scenarios.
Table S4: The average cost of QRA, FIT, colonoscopy.
Table S5: The aggregated costs for each participant.
Table S6: Average Screening cost of difference strategies.
Figure S1: Detection rates of stage I–IV across the four screening strategies.
Figure S2: One‐way sensitivity analysis.
Data Availability Statement
All data are available from the corresponding author upon reasonable request.