Wang SY, Dong XT, Yuan Z, Jin LX, Gao WF, Han YK, Ni KM, Liu ZC, Wang JY, Wei XM, Su XM, Peng X, Zhang CZ. Factors associated with false fecal immunochemical test results in colorectal cancer screening. World J Gastrointest Oncol 2025; 17(4): 101487 [DOI: 10.4251/wjgo.v17.i4.101487]
Corresponding Author of This Article
Chun-Ze Zhang, MD, PhD, Professor, Department of Colorectal Surgery, Tianjin Union Medical Center, No. 190 Jieyuan Road, Hongqiao District, Tianjin 300121, China. chunze.zhang@nankai.edu.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Co-corresponding authors: Xi Peng and Chun-Ze Zhang.
Author contributions: Zhang CZ and Peng X conceived and designed the study and received funding; Zhang CZ, Peng X and Su XM performed data acquisition and collection; Wang SY, Yuan Z and Dong XT did data analysis and interpretations; Wang SY, Jin LX, Gao WF, Han YK and Liu ZC prepared the first draft; Ni KM, Wang JY, Wei XM and Zhang CZ critically revised the manuscript; all authors approved the final manuscript; Wang SY and Dong XT contributed equally to this work as co-first authors. Given the substantial workload involved in data processing and analysis, they collaboratively completed all aspects of the work. Zhang CZ and Peng X contributed equally to this work as co-corresponding authors. They dedicated equal time and effort to the initiation, supervision, and management of the project.
Supported by Natural Science Foundation of Tianjin, No. 21JCZDJC00060 and No. 21JCYBJC00180; Tianjin Health and Medical Science and Technology Project, No. TJWJ2023QN040; and National Key Research and Development Program, No. 2017YFC1700606 and No. 2017YFC1700604.
Institutional review board statement: The study was approved by the Ethics Committee of Tianjin Union Medical Center (Approval No. 2022-803).
Informed consent statement: All participants have signed the informed consent forms.
Conflict-of-interest statement: The authors declare no potential conflict of interests.
Data sharing statement: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Chun-Ze Zhang, MD, PhD, Professor, Department of Colorectal Surgery, Tianjin Union Medical Center, No. 190 Jieyuan Road, Hongqiao District, Tianjin 300121, China. chunze.zhang@nankai.edu.cn
Received: September 16, 2024 Revised: December 10, 2024 Accepted: January 22, 2025 Published online: April 15, 2025 Processing time: 190 Days and 4.6 Hours
Abstract
BACKGROUND
Certain subgroups are at an increased risk of false fecal immunochemical test (FIT) results; however, related studies are limited, and the available evidence is conflicting.
AIM
To evaluate factors associated with false-positive and false-negative FIT results.
METHODS
This retrospective study was based on the database of the Tianjin Colorectal Cancer Screening Program from 2012 to 2020. A total of 4129947 residents aged 40-74 years completed at least one FIT. Of these, 24890 asymptomatic participants who underwent colonoscopy examinations and completed lifestyle questionnaires were included in the analysis. Multivariable logistic regression was performed to identify the factors associated with false FIT results.
RESULTS
Among the overall screening population, 88687 (2.15%) participants tested positive for FIT. The sensitivity, specificity, positive predictive value, and negative predictive value of FIT for advanced neoplasms were 58.2%, 44.8%, 9.7%, and 91.3%, respectively. Older age, female sex, smoking, alcohol consumption, higher body mass index, and hemorrhoids were significantly associated with increased odds of false-positive and lower odds of false-negative FIT results. Moreover, features of high-grade dysplasia or villous for advanced adenoma and the presence of cancer were also associated with lower odds of false-negative results, while irregular exercise and diverticulum were associated with higher odds of false-positive results.
CONCLUSION
FIT results may be inaccurate in certain subgroups. Our results provide important evidence for further individualization of screening strategies.
Core Tip: This comprehensive study, encompassing 4129947 participants, uncovers crucial insights into factors associated with false-positive and false-negative results in fecal immunochemical tests (FITs) for colorectal cancer (CRC) screening. It identifies novel risk factors, such as body mass index, exercise habits, and specific tumor characteristics, shedding light on the need for personalized screening strategies. These findings have significant implications for enhancing the accuracy and effectiveness of FIT-based CRC screening programs.
Citation: Wang SY, Dong XT, Yuan Z, Jin LX, Gao WF, Han YK, Ni KM, Liu ZC, Wang JY, Wei XM, Su XM, Peng X, Zhang CZ. Factors associated with false fecal immunochemical test results in colorectal cancer screening. World J Gastrointest Oncol 2025; 17(4): 101487
Colorectal cancer (CRC) is the third leading cause of cancer-related death[1]. Population-based screening is the most powerful public health tool to reduce CRC incidence and mortality[2,3]. There are multiple recommended screening approaches with varied risks and benefits[4]. Colonoscopy is considered the gold standard for CRC screening due to its high sensitivity and ability to allow simultaneous polypectomy, but it is invasive, costly, and resource-intensive[5]. Sigmoidoscopy, while less invasive, only examines the distal colon and rectum, limiting its efficacy[6]. Stool-based tests, including fecal immunochemical test (FIT), guaiac-based fecal occult blood tests, and multi-target stool DNA tests, are noninvasive, cost-effective, and more acceptable to the population[7].
However, 45%-70% of FIT-positive participants had no advanced neoplasm (AN) according to colonoscopy findings[8-10]. In the Chinese population, FIT accuracy is of particular importance due to the large screening cohort size and the strain on medical resources, which makes efficient stratification critical for reducing unnecessary follow-up procedures[11]. The false-positive rate of FIT in detecting advanced adenoma and CRC tended to be higher, at over 70% in Guangzhou (2019)[12] and approximately 90% in Hangzhou (2020)[13] and Tianjin (2018)[14]. Moreover, in a report from Shanghai (2021), the expected detection rate of CRC among participants with any FIT positive was only 11.7/1000[15]. False-positive results can lead to unnecessary referrals and medical harms linked to follow-up colonoscopy and surveillance, along with extra costs, burden and psychological harm[16,17].
Additionally, up to 10% of participants with a negative FIT appear to have CRC or a precursor lesion[8]. A meta-analysis including 19 studies showed that the FIT is highly specific but moderately sensitive in detecting CRC[18]. In detecting AN, the sensitivity of FIT was below 50% in most reports[10,19-21], implying a considerable proportion of false-negative FITs. These negative results might falsely reassure patients and lead to delayed diagnosis. It has been revealed that the prevalence of metastatic disease was threefold higher among participants with false negative FOBT results[22].
To date, only a few small-scale studies have evaluated risk factors for inaccurate FIT results, especially for false-negative results; moreover, the factors associated with inaccurate FIT results were conflicting among previous studies, hampering the development of recommendations to improve FIT accuracy and screening effectiveness[23,24]. Therefore, this study analyzed data from the Tianjin Colorectal Cancer Screening Program (2012-2020), involving 4.1 million residents aged 40-74 years, to identify factors associated with false FIT results and provide insights to improve FIT accuracy and optimize CRC screening strategies.
MATERIALS AND METHODS
Screening strategy and study population
This large-scale study was conducted under the framework of Tianjin CRC Screening Program, which was initiated in 2012 according to the Technical Plan for Early Diagnosis and Early Treatment of Colorectal Cancer formulated by the National Health Commission of the People’s Republic of China[25]. Briefly, residents aged 40-74 years were preliminarily screened using a high-risk factor questionnaire (HRFQ) or FIT, and in the second step, those with either positive HRFQ or positive FIT were defined as high-risk participants and further recommended to undergo colonoscopy at hospitals designated by the program free of charge[12,14]. All screening-related testing was conducted in CRC screening units designated by the Tianjin Health Commission.
From 2012 to 2020, a total of 5,226,854 community residents aged 40-74 years were recruited for the preliminary screening. Participants without FIT data (n = 1096907) were excluded from the study. Additionally, individuals with symptoms (n = 24397), including 6466 with chronic diarrhea, 9388 with chronic constipation, 2165 with mucus bloody stool, and 6378 with two or more symptoms, were excluded. Participants with incomplete colonoscopy or pathology results (n = 220) or incomplete lifestyle questionnaires (n = 14647) were also excluded. After excluding participants with no FIT data (n = 1096907), 4129947 participants were included in the preliminary screening analysis (Figure 1).
Figure 1 Flow diagram of study selection.
FIT: Fecal immunochemical test.
HRFQ
Participants who had one or more of the following risk factors were defined as HRFQ positive: (1) A family history of first-degree relatives with CRC; (2) A personal history of any cancer; (3) A personal history of colorectal polyps; or (4) Coexistence of at least two of the following syndromes: Chronic diarrhea; chronic constipation; mucus bloody stool; history of chronic appendicitis or appendectomy; history of chronic cholecystitis or cholecystectomy; and history of psychological trauma (e.g., divorce, death of relatives) in the past 20 years.
Fecal immunological tests
A fecal occult blood test was performed using the immunogold method (Abbott Biotechnology Co., Ltd.). With no diet restriction, participants were asked to collect a 10-50 mg stool sample and send it to a screening hospital laboratory within 2 hours after collection. All tests were performed strictly according to the manufacturer's protocol. The FIT positivity threshold was set at 100 ng hemoglobin (Hb)/mL.
Clinical procedures and definitions
All endoscopic examinations were performed by experienced endoscopists who had at least 5 years of experience and were all board certified to perform endoscopy. All abnormal findings were confirmed by expert gastrointestinal pathologists following up-to-date clinical guidelines.
AN was defined as CRC or advanced adenoma ≥ 10 mm in diameter or with villous components or high-grade dysplasia. A false-positive FIT was defined as a positive FIT result without any advanced adenoma or CRC identified by subsequent colonoscopy. A false-negative FIT was defined as a negative FIT result in an individual in whom advanced adenoma or CRC was detected by colonoscopy. The FIT screening procedure typically involves participants collecting stool samples at home following the provided instructions and submitting them to a laboratory for analysis. If the FIT result is positive, further evaluation with a colonoscopy is recommended to confirm the diagnosis and determine the underlying cause.
Smoking status was classified into three categories: Never smoker, current smoker (defined as smoking at least one cigarette per day for a minimum of one year), and former smoker (defined as an individual who previously smoked but has abstained from smoking for at least one year). Alcohol consumption was categorized into two groups: Never drinker and ever drinker. The "never drinker" group included individuals who had never consumed alcohol or drank only occasionally (defined as drinking sporadically but less than once per week on average). The "ever drinker" group was further classified to include current drinkers (defined as individuals who consume alcohol at least once per week on a regular basis) and current non-drinker with past alcohol consumption. Regular exercise was defined as more than 30 minutes of physical activity at least once per week; otherwise, it was classified as ‘irregular exercise’. Overweight was defined as a body mass index (BMI) of 25.0-29.9 kg/m², and obesity as a BMI of ≥ 30.0 kg/m2.
Ethics
The CRC screening protocol was approved by the Health Bureau of Tianjin City. This study was approved by the ethics committee of Tianjin Union Medicine Center. All participants signed written informed consent before information collection and colonoscopy examination. All investigations and methods used were in accordance with the Declaration of Helsinki.
Statistical analysis
Continuous variables are described as the mean with SD, while categorical variables are described as frequencies with percentages. χ2 tests or Fisher’s exact tests were used to compare categorical variables, and one-way ANOVA was used to compare continuous variables. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy and corresponding 95% confidence intervals (95%CIs) were calculated to describe the performance of FIT in predicting colorectal lesions, with the χ2 test performed for comparisons within groups. Multivariable logistic regression analyses were performed to identify factors associated with false-positive and false-negative FITs; odds ratios and 95%CIs were calculated. All analyses were performed using R software (V.4.1.2). P values were calculated to compare differences between groups. For categorical variables, the χ2 test or Fisher’s exact test (when expected frequencies were < 5) was used to assess group differences. For continuous variables, one-way ANOVA or t-tests were employed, depending on the comparison type. Two-sided P values < 0.05 were considered to be statistically significant.
RESULTS
A total of 4129947 eligible participants completed at least one FIT in a preliminary screening from 2012 to 2020 (Figure 1), and their main characteristics according to FIT results are shown in Table 1. Overall, the FIT was positive in 88687 (2.15%) participants. Compared with participants with a negative FIT, those with a positive FIT were more likely to be older, be male, smoke, consume alcohol, exercise regularly and have a higher BMI (all P < 0.05); moreover, they had a significantly higher proportion of chronic diarrhea, chronic constipation and mucus bloody stool (all P < 0.001).
Table 1 Characteristics of participants with complete fecal immunological test data in Tianjin Colorectal Cancer Screening Program, 2012-2020, n (%).
Characteristic
Total (n = 4129947)
Positive FIT (n = 88687)
Negative FIT (n = 4041260)
P value
Age (years), mean ± SD
60.80 ± 8.35
63.14 ± 7.69
60.75 ± 8.36
< 0.001
40-49
460401 (11.1)
5220 (5.9)
455181 (11.3)
< 0.001
50-59
1337212 (32.4)
22160 (25.0)
1315052 (32.5)
60-69
1607369 (38.9)
40561 (45.7)
1566808 (38.8)
70-74
724965 (17.6)
20746 (23.4)
704219 (17.4)
Sex
Male
2197221 (53.2)
46723 (52.7)
2150498 (53.2)
0.002
Female
1932726 (46.8)
41964 (47.3)
1890762 (46.8)
Marital status
Married
3941435 (95.4)
84617 (95.4)
3856818 (95.4)
< 0.001
Unmarried
47806 (1.2)
799 (0.9)
47007 (1.2)
Divorced
29190 (0.7)
598 (0.7)
28592 (0.7)
Widowed
91779 (2.2)
2551 (2.9)
89228 (2.2)
Missing
19737 (0.5)
122 (0.1)
19615 (0.5)
Educational level
Primary school or below
1052467 (25.5)
26043 (29.4)
1026424 (25.4)
< 0.001
Middle school
2621411 (63.5)
55341 (62.4)
2566070 (63.5)
College or above
411895 (10.0)
7011 (7.9)
404884 (10.0)
Missing
44174 (1.1)
292 (0.3)
43882 (1.1)
Occupation
Office clerks and related personnel
158551 (3.8)
2894 (3.3)
155657 (3.9)
< 0.001
Persons in charge of state organizations, large organizations, enterprises and institutions
750333 (18.2)
11083 (12.5)
739250 (18.3)
Soldiers
1555 (0.0)
38 (0.0)
1517 (0.0)
Agriculture workers
1003000 (24.3)
26694 (30.1)
976306 (24.2)
Business and service personnel
286538 (6.9)
3791 (4.3)
282747 (7.0)
Production, transportation, equipment and related personnel
475649 (11.5)
13577 (15.3)
462072 (11.4)
Professional and technical personnel
707738 (17.1)
10571 (11.9)
697167 (17.3)
Others
248457 (6.0)
5777 (6.5)
242680 (6.0)
Unemployed
475567 (11.5)
14130 (15.9)
461437 (11.4)
Missing
22559 (0.5)
132 (0.1)
22427 (0.6)
Smoking status
Never smoker
2003864 (48.5)
41124 (46.4)
1962740 (48.6)
< 0.001
Former smoker
76977 (1.9)
2675 (3.0)
74302 (1.8)
Current smoker
489557 (11.9)
12751 (14.4)
476806 (11.8)
Missing
1559549 (37.8)
32137 (36.2)
1527412 (37.8)
Alcohol consumption
Never drinker
2349521 (56.9)
49412 (55.7)
2300109 (56.9)
< 0.001
Ever drinker
219447 (5.3)
7093 (8.0)
212354 (5.3)
Missing
1560979 (37.8)
32182 (36.3)
1528797 (37.8)
Physical activity
Irregular exercise
1620846 (39.2)
32472 (36.6)
1588374 (39.3)
< 0.001
Regular exercise
948229 (23.0)
24060 (27.1)
924169 (22.9)
Missing
1560872 (37.8)
32155 (36.3)
1528717 (37.8)
BMI (kg/m2)
< 25
1574985 (38.1)
31170 (35.1)
1543815 (38.2)
< 0.001
25-29.9
847303 (20.5)
21280 (24.0)
826023 (20.4)
≥ 30
150992 (3.7)
4276 (4.8)
146716 (3.6)
Missing
1556667 (37.7)
31961 (36.0)
1524706 (37.7)
Chronic diarrhea
No
4012945 (97.2)
77784 (87.7)
3935161 (97.4)
< 0.001
Yes
117002 (2.8)
10903 (12.3)
106099 (2.6)
Chronic constipation
No
3943864 (95.5)
75459 (85.1)
3868405 (95.7)
< 0.001
Yes
186083 (4.5)
13228 (14.9)
172855 (4.3)
Mucus bloody stool
No
4088905 (99.0)
81690 (92.1)
4007215 (99.2)
< 0.001
Yes
41042 (1.0)
6997 (7.9)
34045 (0.8)
Chronic appendicitis/appendectomy
No
4052865 (98.1)
84350 (95.1)
3968515 (98.2)
< 0.001
Yes
77082 (1.9)
4337 (4.9)
72745 (1.8)
Chronic cholecystitis/cholecystectomy
No
4068649 (98.5)
85120 (96.0)
3983529 (98.6)
< 0.001
Yes
61298 (1.5)
3567 (4.0)
57731 (1.4)
Family history of CRC in FDR
No
21415 (0.5)
2168 (2.4)
19247 (0.5)
< 0.001
Yes
4096482 (99.2)
86291 (97.3)
4010191 (99.2)
Unknown
12050 (0.3)
228 (0.3)
11822 (0.3)
Characteristics of the study population
Table 2 summarizes the characteristics of the study population of 24890 asymptomatic participants aged 40-74 years with complete FIT, colonoscopy data and questionnaires related to lifestyle factors. The mean age of the overall population was 62.33 ± 7.58 years; 12147 (48.4%) were aged 60-69 years, 11911 (47.9%) were male, 23907 (96.1%) were married, and 2945 (11.8%) had a college or above education. The FIT was positive in 13811 (55.5%) participants, and colonoscopy detected nonadvanced adenomas in 10529 (42.3%), advanced adenomas in 1780 (7.2%) and cancer in 524 (2.1%) participants.
Table 2 Characteristics of the study population, n (%).
Characteristics
Total (n = 24890)
Participants with no advanced neoplasm (n = 22586)
Participants with advanced neoplasm (n = 2304)
False-positive FIT (n = 12471)
True-negative FIT (n = 10115)
P value
False-negative FIT (n = 964)
True-positive FIT (n = 1340)
P value
Age (years), mean ± SD
62.33 ± 7.58
62.54 ± 7.26
61.57 ± 8.02
< 0.001
63.26 ± 7.49
65.32 ± 6.14
< 0.001
40-49
1734 (7.0)
638 (5.1)
1028 (10.2)
< 0.001
55 (5.7)
13 (1.0)
< 0.001
50-59
6506 (26.1)
3404 (27.3)
2653 (26.2)
229 (23.8)
220 (16.4)
60-69
12147 (48.8)
6194 (49.7)
4746 (46.9)
461 (47.8)
746 (55.7)
70-74
4503 (18.1)
2235 (17.9)
1688 (16.7)
219 (22.7)
361 (26.9)
Sex
Male
11911 (47.9)
5865 (47.0)
4612 (45.6)
0.033
596 (61.8)
838 (62.5)
0.761
Female
12979 (52.1)
6606 (53.0)
5503 (54.4)
368 (38.2)
502 (37.5)
Marital status
Married
23907 (96.1)
11984 (96.1)
9706 (96.0)
< 0.001
928 (96.3)
1289 (96.2)
0.172
Unmarried
210 (0.8)
85 (0.7)
106 (1.0)
6 (0.6)
13 (1.0)
Divorced
175 (0.7)
78 (0.6)
83 (0.8)
10 (1.0)
4 (0.3)
Widowed
540 (2.2)
300 (2.4)
191 (1.9)
18 (1.9)
31 (2.3)
Unknown
58 (0.2)
24 (0.2)
29 (0.3)
2 (0.2)
3 (0.2)
Educational level
Primary school or below
5011 (20.1)
3002 (24.1)
1589 (15.7)
< 0.001
149 (15.5)
271 (20.2)
< 0.001
Middle school
16769 (67.4)
8300 (66.6)
6890 (68.1)
659 (68.4)
920 (68.7)
College or above
2945 (11.8)
1109 (8.9)
1546 (15.3)
149 (15.5)
141 (10.5)
Unknown
165 (0.7)
60 (0.5)
90 (0.9)
7 (0.7)
8 (0.6)
Smoking status
Never smoker
19123 (76.8)
9347 (74.9)
8187 (80.9)
< 0.001
708 (73.4)
881 (65.7)
< 0.001
Former smoker
1100 (4.4)
608 (4.9)
360 (3.6)
49 (5.1)
83 (6.2)
Current smoker
4667 (18.8)
2516 (20.2)
1568 (15.5)
207 (21.5)
376 (28.1)
Alcohol consumption
Never drinker
22262 (89.4)
11034 (88.5)
9298 (91.9)
< 0.001
853 (88.5)
1077 (80.4)
< 0.001
Ever drinker
2628 (10.6)
1437 (11.5)
817 (8.1)
111 (11.5)
263 (19.6)
Physical activity
Irregular exercise
13948 (56.0)
7045 (56.5)
5705 (56.4)
0.903
525 (54.5)
673 (50.2)
0.049
Regular exercise
10942 (44.0)
5426 (43.5)
4410 (43.6)
439 (45.5)
667 (49.8)
BMI (kg/m2)
< 25
14126 (56.8)
6790 (54.4)
6086 (60.2)
< 0.001
582 (60.4)
668 (49.9)
< 0.001
25-29.9
9142 (36.7)
4763 (38.2)
3484 (34.4)
336 (34.9)
559 (41.7)
≥ 30
1622 (6.5)
918 (7.4)
545 (5.4)
46 (4.8)
113 (8.4)
Family history of CRC in FDR
No
23095 (92.8)
12069 (96.8)
8862 (87.6)
< 0.001
883 (91.6)
1281 (95.6)
< 0.001
Yes
1795 (7.2)
402 (3.2)
1253 (12.4)
81 (8.4)
59 (4.4)
Hemorrhoids
No
19105 (76.8)
8950 (71.8)
8350 (82.6)
< 0.001
845 (87.7)
960 (71.6)
< 0.001
Yes
5785 (23.2)
3521 (28.2)
1765 (17.4)
119 (12.3)
380 (28.4)
Diverticulum
No
24333 (97.8)
12152 (97.4)
9938 (98.3)
< 0.001
949 (98.4)
1294 (96.6)
0.008
Yes
557 (2.2)
319 (2.6)
177 (1.7)
15 (1.6)
46 (3.4)
Colonoscopy findings
Normal
12057 (48.4)
6566 (52.7)
5491 (54.3)
0.015
Nonadvanced adenoma
10529 (42.3)
5905 (47.3)
4624 (45.7)
Advanced neoplasm
2304 (9.3)
964 (100.0)
1340 (100.0)
-
Advanced adenoma
1780 (7.2)
688 (71.4)
1092 (81.5)
< 0.001
CRC
524 (2.1)
276 (28.6)
248 (18.5)
< 0.001
Stage 0-I
154 (0.6)
64 (6.6)
90 (6.7)
0.001
Stage II-IV
370 (1.5)
212 (22.0)
158 (11.8)
0.001
False-positive FIT was found in 12471 (55.2%) participants without AN, and false positives were more frequent in participants with an older age, who were male, who smoked, who consumed alcohol, who were overweight, and who had hemorrhoid, diverticulum or nonadvanced adenoma found at colonoscopy (all P < 0.05). A false-negative FIT was found in 964 (31.1%) participants with AN and was more frequent in participants who were younger, nonsmokers, nondrinkers, normal weight, irregular exercisers, and free from hemorrhoid, diverticulum and free of cancer at colonoscopy (all P < 0.05).
Performance of the fecal immunological test
The performance of FIT for detecting colorectal lesions is described in Table 3. The sensitivity of FIT for nonadvanced adenoma, advanced adenoma, and cancer was 61.3%, 56.1%, and 47.3%, respectively; specificity was 45.5%, 45.5% and 44.3%, respectively; PPV was 14.3%, 47.3% and 1.8%, respectively; and NPV was 88.9%, 54.3% and 97.5%, respectively. Moreover, FIT had a higher sensitivity (58.4% vs 42.7%) and similar specificity (44.3% vs 43.3%) for detecting stage 0-I compared to stage II-IV cancer.
Table 3 Performance of fecal immunological test for detecting colorectal lesions.
Lesions
Sensitivity (95%CI)
Specificity (95%CI)
PPV (95%CI)
NPV (95%CI)
Accuracy (95%CI)
Nonadvanced adenoma
61.3 (59.1-63.6)
45.5 (44.7-46.4)
14.3 (13.5-15.0)
88.9 (88.1-89.6)
47.6 (47.6-47.6)
Advanced adenoma
56.1 (55.1-57.0)
45.5 (44.7-46.4)
47.3 (46.5-48.2)
54.3 (53.3-55.3)
50.5 (50.5-50.5)
Colorectal cancer
47.3 (43.1-51.6)
44.3 (43.7-45.0)
1.8 (1.6-2.0)
97.5 (97.2-97.8)
44.4 (44.4-44.4)
Stage 0-I
58.4 (50.7-66.2)
44.3 (43.7-45.0)
0.7 (0.5-0.8)
99.4 (99.3-99.6)
44.4 (44.4-44.4)
Stage II-IV
42.7 (37.7-47.7)
44.3 (43.7-45.0)
1.2 (1.0-1.3)
98.1 (97.8-98.3)
44.3 (44.3-44.3)
Advanced neoplasm
58.2 (56.1-60.2)
44.8 (44.1-45.4)
9.7 (9.2-10.2)
91.3 (90.8-91.8)
46.0 (46.0-46.0)
Any neoplasm
56.5 (55.6-57.3)
45.5 (44.7-46.4)
52.5 (51.6-53.3)
49.6 (48.6-50.5)
51.2 (51.2-51.2)
The test performance according to the participants’ characteristics is shown in Supplementary Table 1. Older participants had higher sensitivity and PPVs, while younger participants had higher specificity and NPVs; the accuracy of FIT increased with age among those older than 50 years (from 44.2% in the 50-59 years group to 45.5% in the 70-74 years group), whereas it was highest (60.0%) in the 40-49 years group. Compared to males, females had a similar sensitivity (57.7% vs 58.4%, P = 0.761) but a higher specificity (45.4% vs 44.0%, P = 0.032) of FIT. In addition, a higher sensitivity and a lower specificity were found in current or former smokers, ever alcohol consumers, obese participants, those with regular exercise and those without hemorrhoids or diverticula.
Factors associated with false-positive and false-negative FIT results
Multivariable logistic regression analyses were performed to identify factors associated with false FIT results (Table 4). Older age, current or former smoking, ever alcohol consumption, higher BMI, and the presence of hemorrhoids or diverticula were significantly associated with increased odds of false-positive FIT results, whereas male sex and regular exercise were significantly associated with lower odds of false-positive results.
Table 4 Factors associated with false-positive and false-negative fecal immunological test for the detection of advanced colorectal neoplasm.
Variables
False-positive FIT (true negative as reference)
False-negative FIT (true positive as reference)
Crude OR (95%CI)
Adjusted OR (95%CI)
P value
Crude OR (95%CI)
Adjusted OR 95%CI)
P value
Age (per additional year)
1.02 (1.01-1.02)
1.01 (1.01-1.02)
< 0.001
0.96 (0.94-0.97)
0.96 (0.94-0.97)
< 0.001
Sex
Female
1
1
1
1
Male
1.06 (1.01-1.12)
0.91 (0.85-0.96)
0.001
0.97 (0.82-1.15)
1.23 (1.00-1.49)
0.045
Smoking status
Never smoker
1
1
1
1
Former smoker
1.48 (1.29-1.69)
1.39 (1.21-1.60)
< 0.001
0.73 (0.51-1.06)
1.03 (0.68-1.55)
0.881
Current smoker
1.41 (1.31-1.51)
1.36 (1.26-1.48)
< 0.001
0.69 (0.56-0.83)
0.73 (0.57-0.95)
0.017
Never drinker
1
1
1
1
Ever drinker
1.48 (1.35-1.62)
1.3 (1.17-1.44)
< 0.001
0.53 (0.42-0.68)
0.60 (0.45-0.81)
< 0.001
Physical activity
Irregular exercise
1
1
1
1
Regular exercise
1.00 (0.95-1.05)
0.90 (0.85-0.95)
< 0.001
0.84 (0.71-10)
1.07 (0.88-1.31)
0.474
BMI (kg/m2)
< 25
1
1
1
1
25-29.9
1.23 (1.16-1.30)
1.18 (1.11-1.25)
< 0.001
0.69 (0.58-0.82)
0.75 (0.61-0.91)
0.004
≥ 30
1.51 (1.35-1.69)
1.42 (1.27-1.59)
< 0.001
0.47 (0.33-0.67)
0.56 (0.38-0.83)
0.004
Hemorrhoid
No
1
1
1
1
Yes
1.86 (1.74-1.99)
1.85 (1.73-1.97)
< 0.001
0.36 (0.28-0.45)
0.58 (0.46-0.74)
< 0.001
Diverticulum
No
1
1
1
1
Yes
1.47 (1.22-1.77)
1.26 (1.04-1.52)
0.018
0.44 (0.25-0.80)
0.75 (0.41-1.39)
0.359
Presence of nonadvanced adenoma
No
1
1
Yes
1.07 (1.01-1.13)
0.99 (0.94-1.05)
0.753
Presence of any advanced adenoma ≥ 10 mm
No
1
1
Yes
0.21 (0.18-0.25)
0.08 (0.06-0.12)
< 0.001
Presence of any advanced adenoma of high-grade dysplasia
No
1
1
Yes
0.68 (0.49-0.94)
0.66 (0.45-0.98)
0.041
Presence of any advanced adenoma with villous/tubulovillous features
No
1
1
Yes
0.62 (0.40-0.97)
0.76 (0.44-1.31)
0.248
Presence of CRC
No
1
1
Stage 0-I CRC
1.13 (0.81-1.58)
0.13 (0.08-0.22)
< 0.001
Stage II-IV CRC
2.13 (1.70-2.67)
0.26 (0.17-0.39)
< 0.001
With regard to the false-negative FIT results, older age, current smoking, ever alcohol consumption, higher BMI and the presence of hemorrhoids, advanced adenoma of high-grade dysplasia, advanced adenoma with villous/tubulovillous features or cancer were significantly associated with lower odds of false-negative FIT results, whereas males were more likely to have false-negative results.
DISCUSSION
Improving the accuracy of fecal tests could increase the effectiveness of CRC screening programs. In our large-scale study involving 24890 asymptomatic participants, we found that older age, female sex, smoking, alcohol consumption, higher BMI, and hemorrhoids were significantly associated with increased odds of false-positive and lower odds of false-negative FIT results. Moreover, features of high-grade dysplasia or villous for advanced adenoma and the presence of cancer were also associated with lower odds of false-negative results, while irregular exercise and diverticulum were associated with higher odds of false-positive results. These findings highlight the complexity of factors influencing FIT accuracy and underscore the importance of tailoring CRC screening approaches to specific subpopulations. To the best of our knowledge, our study is the first of this size to investigate the risk factors associated with inaccurate FIT results.
Over the past decade, the two-step CRC screening strategy has been implemented in several regions of China, such as Guangzhou, Shanghai, and Zhejiang. In the present study, the PPVs of FIT for detecting CRC were 2.15%, which is comparable to 2.7% in Zhejiang[26], 1.2% in Shanghai[15], and 3.5%-4.9% in Guangzhou[12,27]. Our data also showed a 9.7% PPV for detecting AN, which is comparable to 8.9% in Zhejiang[26] and 12.5% for detecting precancerous lesions in Shanghai[15] but lower than 23.8% in Guangzhou[12]. Such regional variations could reflect differences in population characteristics, screening protocols, or diagnostic thresholds, which warrant further investigation to optimize CRC screening strategies in diverse settings. In addition, a PPV of 53.2% in detecting any neoplasms was reported in another study in Guangzhou[15], and our data (52.5%) were consistent with this finding.
Similar to our findings, Wong et al[28] demonstrated that older participants had a higher risk of false-positive results and a lower risk of false-negative results. Moreover, this increased risk of false positives was found by Kim et al[29]. In contrast, Stegeman et al[30] reported a significantly higher risk of a false-negative results in individuals with an older age, and several other studies reported no association between age and false-positive[30,31] or false-negative results[29,32]. The high positive rate could be related to the higher average fecal hemoglobin content in older participants[33]. Given these conflicting findings, further studies are needed to explore age-specific variations in FIT accuracy, particularly in older populations.
In our study, males were found to be at a lower risk of false-positive results and at a higher risk of false-negative results, which was in line with the results of a meta-analysis[34]. However, findings were inconsistent among previous studies, with some studies reporting a higher risk of false-positive results for males[30,34], some reporting a lower risk of false-negative[32] or false-positive results[31] for males, and some reporting no association[28,29]. Possible explanations for the low FIT false positivity in males could be partially related to the higher prevalence of colorectal neoplasms[35]. These inconsistencies might arise from differences in study populations, screening protocols, or analytical methods, emphasizing the need for standardized research approaches in this area. Additionally, due to a higher proportion of right-sided carcinoma in females[36], as well as longer colon length and transit time[37], bleeding caused by neoplasms was less likely to be detected by FIT. Ibáñez-Sanz et al[31] demonstrated that the high FIT false-positivity in females could not be explained by anal disorders, medication use, anemia or menstruation. Nevertheless, the potential factors underlying the observed sex differences in false positivity remain unknown.
Studies assessing the association between false FIT results and hemorrhoids or diverticula are limited[29-31]. In our study, participants with hemorrhoids or diverticula were found to be at significantly higher risk of false-positive results, which was in line with some previous studies[29,31]. A meta-analysis[8] and an individual study[30] showed no association with false FIT results for hemorrhoids or diverticula; however, only two of the studies included in the meta-analysis assessed these factors. This indicates a need for more comprehensive investigations to confirm these findings. Fecal hemoglobin detected by FIT is not tumor-specific but can result from any cause of lower gastrointestinal bleeding, such as hemorrhoid and diverticula. Clinicians should be aware of this limitation, as it may lead to unnecessary colonoscopies in affected subpopulations, posing a potential burden on healthcare resources.
Few studies have evaluated whether the accuracy of FIT may differ on the basis of tumor characteristics. In our study, advanced adenoma ≥ 10 mm was significantly associated with a lower risk of false-negative results, which was consistent with results from Chiu et al[38] but was contrary to those from Kim et al[29], who demonstrated a significantly higher risk of false negativity; Wong et al[28] showed no impact on false-negative FITs for adenomas ≥ 10 mm. Larger adenomas appear to have increased vascularity and larger surfaces in contact with feces. A larger size has been indicated to be independently associated with a higher concentration of fecal hemoglobin[33]. In addition, consistent with previous studies[28,29], we found a lower risk of false-negative results for adenoma of high-grade dysplasia but found no association for villous/tubulovillous features; among populations without ANs, the presence of nonadvanced adenoma (< 10 mm) did not increase the risk of false-positive results. These findings suggest that tumor size and pathological features play a crucial role in FIT accuracy, warranting further exploration of these factors to enhance screening effectiveness.
Smoking, alcohol consumption and higher BMI are all known risk factors for CRC, and these lifestyle factors have been considered in risk stratification for colonoscopy screening, especially BMI and/or smoking[39-41]. Contrary to our study and that of Wong et al[28], Stegeman et al[30] demonstrated that smoking was associated with false-negative results, and both smoking and BMI did not reach significance in the study of Kim et al[29]. Physical inactivity was also a risk factor for CRC but has not been addressed previously. We found that participants with regular exercise had a higher sensitivity of FIT and were less likely to have a false-positive result.
This study had some limitations. First, due to its observational design, this study is prone to confounding. Second, the exposures were based on self-reports and might include some misclassification. Third, the data were collected in Tianjin, China, and cannot represent the whole country. Fourth, the data on the use of aspirin or anticoagulant drugs that could be possible confounders were not available; however, a meta-analysis showed no systematic effect on FIT false positivity, with nine out of ten included studies reporting that the use of anticoagulants does not increase FIT false positivity[8]. Fifth, the quantitative FIT test is not practical for CRC screenings in China due to the higher cost. Thus, strategies to reduce the cost and improve the accessibility of quantitative FIT tests should be prioritized. In addition, further studies are encouraged to investigate novel biomarkers or combined testing approaches that could complement FIT and enhance its diagnostic accuracy.
CONCLUSION
In conclusion, FIT results may be inaccurate in certain subgroups. Participants who are at a higher risk of inaccurate FIT results should be more cautiously considered in CRC screening with the use of other approaches; in addition, a specific cutoff value of FIT or a specific initiation age for screening should be considered in certain subpopulations. Future studies should focus on refining FIT algorithms and integrating additional biomarkers to improve test accuracy, particularly in populations at a higher risk of false results. Our findings could provide important evidence for further individualization of screening strategies that could target more subgroups with a high risk of false FIT results.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Oncology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B, Grade B
Novelty: Grade B, Grade B
Creativity or Innovation: Grade B, Grade B
Scientific Significance: Grade A, Grade B
P-Reviewer: Wang H; Wang L S-Editor: Lin C L-Editor: A P-Editor: Zhang L
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