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Utility of fecal immunochemical test vs guaiac fecal occult blood test for assessment of gastrointestinal bleed in hospitalized patients
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Utility of fecal immunochemical test vs guaiac fecal occult blood test for assessment of gastrointestinal bleed in hospitalized patients ⁎
AbdulRazaq Sokoroa,b,d, , Leigh Anne Shafera, Mitchell Darrc, Harminder Singha a
Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada c Department of Family Medicine, University of Manitoba, Winnipeg, Manitoba, Canada d Shared Health Diagnostic Services, Winnipeg, Manitoba, Canada b
A R T I C LE I N FO
A B S T R A C T
Keywords: FIT Hospital patients GI bleeding gFOBT Fecal occult blood
Background: Guaiac fecal occult blood testing (gFOBT) is often used “off-label” for gastrointestinal (GI) bleeding. Fecal Immunochemical Test (FIT) is increasingly replacing gFOBT in colorectal cancer screening and may play a role in assessment for significant bowel disease. We examined the concordance of FIT with gFOBT (Hemoccult Sensa II) among inpatients and between day 1 and day 3 gFOBT results. Methods: FIT was performed alongside gFOBT on all inpatient stool sent for occult blood to the Winnipeg Health Sciences Centre laboratory over 1 y. gFOBT was performed on days 1 and 3 post stool collection, while FIT was performed on day 1 only. Results: Positivity rates were highest for Day 1 gFOBT (27.7%), and lowest for FIT (18.3%). Concordance between FIT and Days 1 and 3 gFOBT for negative test results (96.4% and 94.1%) was significantly higher than that expected by chance alone (58.7% and 61.3%, P < .001). Similarly, concordance for positive test results (55.8% and 55.6%) was significantly higher as well as for days 1 and 3 gFOBT results. Conclusions: We found no benefit in delayed testing for 3 days post collection. FIT provides equivalent results to gFOBT in hospitalized patients.
1. Introduction Fecal test for occult blood (FOBT) is used as a screening test for Colorectal Cancer (CRC), which has led to a decrease in incidence and mortality of CRC when used in conjunction with additional testing strategies (such as colonoscopy) [1–3]. However, FOBT is often used “off-label” in the inpatient setting to detect the presence or absence of a gastrointestinal (GI) bleed in symptomatic patients [4,5]. In this case, FOBT is used to assist clinical judgement, in order to determine whether additional diagnostic testing/interventions (such as gastrointestinal endoscopy) should be performed or not. There is an increasing interest in the use of the fecal immunochemical test (FIT) to triage patients with gastrointestinal symptoms. However, the criteria used for FOBT in the outpatient screening setting may not be suitable for the inpatient or symptomatic populations, as these populations often require both emergency ordering of the test, and rapid test results [5–9]. As it stands, the current standards for FOBT in place in many laboratories may not meet these criteria. There are many types of FOBT on the market. Hospital laboratories
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in many jurisdictions, currently employ the guaiac FOBT (gFOBT; Hemocult II Sensa, Beckman Coulter, Inc.), which detects the peroxidase-like activity of heme within stool [2,10]. However, this property is also present in non-human sources of hemoglobin as well as plant peroxidases, which can lead to false positive test results [10]. As such, the gFOBT requires that the patient undergoes dietary restriction of foods containing these factors (such as red meats, and certain raw fruits and vegetables) for 3 days prior to stool specimen collection. As an extra precaution or alternatively, development of the gFOBT is held for 3 days after arrival at the laboratory, to allow for degradation of the plant peroxidases and to ensure adequate natural dehydration/drying of the stool sample as wet mounts could produce false positive results. In addition, certain medications have been shown to interfere with the gFOBT, such as high doses of vitamin C, which can lead to a false negative test result [11]. Also, as occult GI bleeding (such as bleeding due to CRC) may be intermittent, the sensitivity of an individual gFOBT is relatively poor. As a result, the gFOBT requires multiple sampling (3 stool specimens over 3 consecutive days) to improve sensitivity. However, multiple sampling, patient dietary and medication restriction, and
Corresponding author at: 1502 – 155 Carlton Street, Winnipeg, MB R3C 3H8, Canada. E-mail address: [email protected] (A. Sokoro).
https://doi.org/10.1016/j.cca.2019.10.017 Received 30 July 2019; Received in revised form 29 September 2019; Accepted 18 October 2019 0009-8981/ © 2019 Elsevier B.V. All rights reserved.
Please cite this article as: AbdulRazaq Sokoro, et al., Clinica Chimica Acta, https://doi.org/10.1016/j.cca.2019.10.017
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2.2. Data analysis
time lag until test result availability reduce the utility of gFOBT in the inpatient setting. Previous studies have indeed suggested overall limited utility of positive gFOBT in inpatient settings [5,12–14]. However individual clinicians continue to find it useful for ruling out the presence of active GI bleeding [15], which maybe particularly useful when the presence or absence of GI bleeding cannot be determined otherwise (e.g black stools and increased plasma urea, for which there could be other etiologies and therefore the presence of GI bleeding is uncertain). There are no data on correlation between day 1 and day 3 gFOBT results in the inpatient setting and most laboratories do not provide gFOBT results on the day the test is ordered. There are no data on correlation between day 1 and day 3 Hemoccult Sensa gFOBT results. The Fecal Immunochemical Test (FIT) is a relatively new version of FOBT. FIT uses antibodies specific for human-globin chain content in stool, and therefore is less likely to be affected by plant peroxidases, non-human sources of hemoglobin, and medications [2,4,16]. FIT has been found to have greater sensitivity than gFOBT for CRC screening, and therefore does not require multiple sampling to accurately detect GI blood loss [17]. However, FIT is a more expensive assay than gFOBT, and results can be affected by exposure to extremes in temperature. In addition, the utility of FIT in assessing an upper GI bleed has been questioned, as hemoglobin is degraded by stomach acid during its passage along the GI tract [2,18]. Despite these issues, FIT is thought to be of greater utility than gFOBT in the outpatient setting, and has been adopted by CRC screening programs in several jurisdictions [3,19]. In addition, there is increasing interest in using FIT to triage symptomatic patients and avoid low yield colonoscopies. Due to the apparent strengths of FIT over gFOBT (one time sampling, reduced requirement for dietary/medication restriction, reduced time until test result availability) in the outpatient setting, comparability of FIT and gFOBT (or better performance of FIT) for the inpatient population could lead to potential replacement of gFOBT in all settings by FIT.
All study data were collected and managed using REDCap electronic data capture tools hosted at University of Manitoba [20]. Standard descriptive statistical analysis was performed. The positivity rates and concordance between Day 1 gFOBT, Day 3 gFOBT, and FIT results were compared using contingency tables. The percent agreement between each type of FOBT, including the percent agreement based on FOBT result was determined using Cohen's kappa coefficient. In patients that received an endoscopy, only endoscopies performed within 7 days prior to or up to 90 days post stool specimen collection were included in analysis, in order to relate the FOBT results to the endoscopy findings. Patient endoscopies that identified findings considered to be high-risk for gastrointestinal bleeding (such as gastrointestinal malignancy, arteriovenous malformation, inflammatory bowel disease, mass, stricture, ulcer, esophagitis, varices, and active bleeding) were considered positive for further analysis. For patients that submitted multiple stool specimens for fecal occult blood testing, each specimen was compared to the corresponding endoscopy results and included in analysis. As well, patients with multiple endoscopy results were considered to have an overall positive endoscopy result if they contained at least 1 relevant finding. The patient endoscopy data was compared between the Day 1 gFOBT, Day 3 gFOBT, and FIT results using contingency tables. All of the above analyses utilized the manufacturer's recommended value of ≥100 ng hg/ml as the cut-off for a positive FIT outcome. In addition, the outcomes for FIT were evaluated at cut-off concentrations less than or greater than the manufacturer's recommended value using receiver operating characteristic (ROC) analysis. ROC curves were generated by plotting sensitivity against 1-specificity of FIT results, using in patient gFOBT results as a surrogate for a gold standard outcome. The research study was approved by the University of Manitoba Health Research Ethics Board. 3. Results
2. Materials & methods 3.1. Patient demographics and management 2.1. Study design During the study period, 135 patient records were reviewed. One patient record was excluded from analysis, due to the absence of hospital admission, leaving 134 patient records included in analysis. Each patient was unique i.e. only had one hospital admission included in the study. Of all patients included in analysis, 104 patients (77.61%) had 1 stool specimen collection sent for FOBT, 11 patients (8.21%) had 2 stool specimen collections sent for FOBT, 18 patients (13.43%) had 3 stool specimen collections sent for FOBT, and 1 patient (0.75%) had 4 stool specimen collections sent for FOBT throughout the course of their hospital encounter. This yielded 155 Day 1 gFOBT results, 184 Day 3 gFOBT results, and 180 FIT results for analysis. 14 patients (10.45%) did not have any Day 1 gFOBT results available. The patient cohort was 58% male, and patient age on admission ranged from 0 (newborn) − 94.5 years old (median age 49.81). While 21 patients (16%) were found to be NPO status at the time of stool specimen collection, 0 patients (0%) were found to have a diet restriction initiated 72 h prior to at least 1 stool specimen collection for FOBT. Of the patients included in analysis, 28 patients (20.90%) were found to have at least 1 positive FIT result, 39 patients (29.10%) were found to have at least 1 positive Day 1 gFOBT result, and 37 patients (27.61%) were found to have at least 1 positive Day 3 gFOBT result. Of the patients with at least 1 positive FIT result, 7 (25.00%) underwent endoscopy within 7 days prior to or up to 90 days post stool specimen collection.
In order to compare FIT to gFOBT, a commercial quantitative FIT (Eiken Chemical Company Ltd.) was introduced to the Health Sciences Centre (HSC) laboratory. During the study period from February 2014 to February 2015, all inpatient stool specimens sent for occult blood were automatically assigned a FIT assay in addition to the usual gFOBT. For these specimens, the gFOBT was performed alongside FIT on Day 1 (i.e., the day that the specimen was collected). The stool specimen was also applied to a second gFOBT card on Day 1, which was held until development on Day 3, to allow for the natural drying of the stool and degradation of plant peroxidases (as per laboratory protocols). The FIT and Day 3 gFOBT results were then entered into the laboratory information system (LIS) and released to the ordering physician simultaneously after the Day 3 gFOBT results became available. The Day 1 gFOBT results were recorded in a study binder in the laboratory, and were not released to the ordering physician. FIT results were recorded as a numerical value in ng of hemoglobin per ml (ng hg/ml), while gFOBT results were recorded as a qualitative (positive/negative) result. In cases where the FIT result exceeded the manufacturer's recommendation for the upper limit of accurate hemoglobin detection (upper limit of quantitation, > 1000 ng hg/ml), the FIT result was recorded as > 1000 ng hg/ml. A retrospective chart review was performed on patients that had at least 1 FIT and 1 Day 3 gFOBT result available. Study data collected during chart review included: patient demographic information, details and indications related to the FOBT order, patient medication status, patient’s laboratory values prior to FOBT specimen collection, details related to patient management, and patient endoscopy details.
3.2. Positivity and concordance of Day 1 gFOBT, Day 3 gFOBT and FIT Table 1 illustrates the outcomes of the Day 1 gFOBT, Day 3 gFOBT, and FIT assays. Of all the FOBTs performed, 43 of Day 1 gFOBTs were 2
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Table 1 Positivity rates of Day 1 gFOBT, Day 3 gFOBT, and FIT. FIT assay is considered positive for values ≥100 ng hg/ml buffer. Test
Positive Results
Negative Results
Total
Day 1 gFOBT Day 3 gFOBT FIT
43 (27.74%) 45 (24.46%) 33 (18.33%)
112 (72.26%) 139 (75.54%) 147 (81.67%)
155 (100%) 184 (100%) 180 (100%)
Table 3 Comparison of Day 1 gFOBT vs Day 3 gFOBT results. Day 1 gFOBT Result
Positive Negative Total
FIT = Fecal Immunochemical Test. gFOBT = guaiac Fecal Occult Blood Test.
Day 3 gFOBT Result Positivee
Negativef
Total
33 (86.84%) 5 (13.16%) 38 (100%)
10 (8.55%) 107 (91.45%) 117 (100%)
43 (27.74%) 112 (72.26%) 155 (100%)
e ,f Expected agreement among gFOBT positive results is found by multiplying the total percent positive for gFOBT by the total percent positive for FIT. Expected agreement among gFOBT negative results is found by multiplying the total percent negative for gFOBT by the total percent negative for FIT. FIT = Fecal Immunochemical Test. gFOBT = guaiac Fecal Occult Blood Test.
positive (27.74% positivity: [43/155] × 100), 45 of Day 3 gFOBTs were positive (24.46% positivity: [45/184] × 100), 33 of FITs were positive (18.33% positivity: [33/180] × 100). Table 2 shows the concordance between the gFOBT and FIT results. Comparison of FIT and Day 1 gFOBT results show that while the concordance among negative results (96.36%) is larger than that expected by chance (58.7%), the concordance among positive results is more striking. Because a positive test is relatively rare, expected agreement (by chance) is just 5.1%. Actual agreement was 44.19−9-times larger than that expected by chance. Similarly, comparison of FIT and Day 3 gFOBT results show that while the concordance among negative results (94.07%) is larger than that expected by chance (61.3%), the concordance among positive results (55.56%) is over 10-times larger than that expected by chance (4.6%). Table 3 shows comparison of Day 1 and Day 3 gFOBT. Results show high degree of concordance for negative results (91.45%), and positive results (86.84%). Comparing FIT, Day 1 and Day 3 gFOBT, we found that 11% of people tested positive on all three tests. Table 4 illustrates the agreement between the Day 1 gFOBT, Day 3 gFOBT, and FIT results. Agreement between FIT and Day 1 gFOBT was found to be statistically significant at 84.97% (P < .001), agreement between FIT and Day 3 gFOBT was found to be statistically significant at 84.44% (P < .001), and agreement between Day 1 and Day 3 gFOBT was found to be statistically significant at 90.32% (P < .001).
Table 4 Percent agreement between FOBT results. Test
Agreement
Expected Agreement
P-value (Cohen’s kappa)a
FIT vs Day 1 gFOBT FIT vs Day 3 gFOBT Day 1 gFOBT vs Day 3 gFOBT
84.97% 84.44% 90.32%
63.88% 65.83% 61.34%
< 0.001 < 0.001 < 0.001
FIT = Fecal Immunochemical Test. gFOBT = guaiac Fecal Occult Blood Test. a Tests whether the agreement in tests is statistically significantly larger than the agreement expected by chance.
Fig. 1 illustrates the ROC curves of FIT compared to Day 1 and Day 3 gFOBT. The overall agreement between FIT and gFOBT, using all FIT result values as a cut-off for a positive FIT outcome, was greatest between FIT and Day 1 gFOBT (Area under the curve = 0.8358, Fig. 1A), compared to FIT and Day 3 gFOBT (AUC = 0.7824). The individual FIT cut-offs that showed the greatest agreement between FIT and Day 1 gFOBT (85.62% agreement) occurred at values of 98, 137, and 358 ng hg/ml. In contrast, the individual FIT cut-offs that showed the greatest agreement between FIT and Day 3 gFOBT (85.00% agreement) occurred at values of 156, 216, 295, 358, 584 ng hg/ml (Fig. 1B).
chart (14.63%), overt GI bleeding (13.73%), melena/black stool (12.24%), GI symptoms (11.64%), and non-bloody diarrhea (5.57%). Less common indications for ordering of FOBT included iron deficiency (1.49%), CRC screening (1.49%), and FOBT ordering prior to initiating anticoagulants (0.30%). Table 6 indicates the percent agreement between FOBT results based on indications for FOBT ordering. Comparison of FIT and day 1 gFOBT was found to have more agreement than would be expected by chance for the indications of: anemia (by lab values), anemia (by patient chart), melena/black stool, overt GI bleeding, and GI symptoms (P < .001 for each indication). Comparison of FIT and Day 3 gFOBT was found to have more agreement than would be expected by chance for the indications of: anemia (by lab values), anemia (by patient chart), melena/black stool, overt GI bleeding, and GI symptoms (P < .001 for each indication). Comparison of Day 1 and Day 3 gFOBT was also found to have more agreement than would be expected by chance for the indications of: anemia (by lab values), anemia (by patient chart), melena/black stool, overt GI bleed, and GI symptoms (P < .001 for each indication), as well as for the indication of iron deficiency (P < .01).
3.4. Indications for FOBT order and stool specimen collection
3.5. Endoscopy findings
Table 5 illustrates the indications for FOBT ordering. The most common indications for ordering of FOBT included anemia indicated by the patient's most recent hemoglobin lab values within 48 h prior to stool specimen collection (35.22%), anemia documented in the patient
Of all the patients in the study, 20 patients (14.93%) received an endoscopy within 7 days prior to or up to 90 days following stool specimen collection for FOBT. Of these, 2 patients (10.00%) had 2 types of endoscopy performed on the same day. Of the 22 total endoscopies
3.3. Receiver operating characteristics analysis
Table 2 Comparison of FIT results. FIT assay is considered positive for values ≥ 100 ng hg/mL buffer. FIT Result
Day 1 gFOBT Result Positive
Positive Negative Total
a
24 (55.81%) 19 (44.19%) 43 (100%)
Day 3 gFOBT Result Negative
b
4 (3.64%) 106 (96.36%) 110 (100%)
Total
Positivec
Negatived
Total
28 (18.30%) 125 (81.70%) 153 (100%)
25 (55.56%) 20 (44.44%) 45 (100%)
8 (5.93%) 127 (94.07%) 135 (100%)
33 (18.33%) 147 (81.67%) 180 (100%)
a ,b,c,d Expected agreement among gFOBT positive results is found by multiplying the total percent positive for gFOBT by the total percent positive for FIT. For example, expected agreement among gFOBT positive results is: (43/153)*(28/153) = 5.1%. Expected agreement for each of the 4 gFOBT groupings above are: (a) 5.1%, (b) 58.7%, (c) 4.6%, and (d) 61.3%.%. FIT = Fecal Immunochemical Test. gFOBT = guaiac Fecal Occult Blood Test.
3
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days 1 and Day 3. This suggests that, the three day waiting period may not be necessary even when there is no diet restriction. One potential explanation for this could be the amount of interferents present in inpatients is not significant enough to impact the assay performance. Another potential explanation could be that among a population with a high positive rate of gFOBT, the study population is enriched with those with higher gastrointestinal bleeding, where the waiting time may not be necessary. A third potential explanation is the use of higher sensitivity gFOBT Hemoccult Sensa in our study. Overall, our study results suggest there is no need to hold specimens in the inpatient setting, especially when using Hemoccult Sensa-this should be incorporated into standard operating procedures of the laboratories. We found that gFOBT and FIT show high concordance for both negative and positive results, in comparison to that expected by chance alone. As expected, given that the majority (79% and 72%) of FIT and Day 3 gFOBT test results were negative, there was a higher FIT/gFOBT concordance among negative than positive gFOBT results. Although 94% of negative Day 3 gFOBT results were also FIT negative (94% concordance among gFOBT negative tests), a somewhat smaller percent of FIT negatives were Day 3 gFOBT negative (86% concordance among FIT negative tests). This, nonetheless, suggests that FIT may be suitable for a rule out strategy, which is clinically helpful in the context of black stools and increased plasma urea, when the presence of GI bleeding is uncertain. This finding is consistent with previous studies [12,23]. Increasingly as per discussion with physicians using FOBT in the inpatient setting, FOBT is primarily used as a rule out test in the inpatient setting, where our study suggests FIT could replace the guaiac FOBT. There is some controversy on whether FIT can be used in upper GI bleed [17,24]. We found in our study a statistically significant agreement by FIT for melena, suggesting that that FIT may be suitable for evaluation of upper GI bleeds. In order not to influence physician behaviour (bias towards FIT results), both FIT and Day 3 results were released together on day 3, although FIT results being ready on Day 1. Despite this, most endoscopies were performed before the FOBT results were available indicating that the test was not being used to assist in clinical decisionmaking. Also, many positive gFOBT results were ignored (patients did not receive endoscopy). This indicates that clinical management was not influenced by the test results and is consistent with previous findings [14,15,25]. However, prior studies have not been able to evaluate the role of same day FOBT testing. It will be interesting to see in future studies, if there is greater reliance on the FOBT results, if they are available on the same day as ordered. Our study results should be interpreted in the context of strengths and limitations. This is a relatively large study performed in an usual practice setting and, hence, results are likely generalizable to other hospitals. However, not everyone in the study underwent other gastrointestinal evaluation tests. Therefore, we cannot compare the results of fecal testing with endoscopy findings for all.
A: FIT vs Day 1 gFOBT (AUC=0.8358)
B: FIT vs Day 3 gFOBT (AUC=0.7824) Fig. 1. Receiver operating characteristics plot of FIT results vs gFOBT results.
performed, 9 (40.91%) were considered positive, due to findings that were considered high-risk for GI bleeding. Table 6 illustrates the FOBT results and endoscopy findings for patients with a positive endoscopy result. The most common findings identified in positive endoscopies include: ulcer (33.33%), stricture (13.33%), and esophagitis (13.33%). Less common findings identified in positive endoscopies include: active bleeding (6.67%), mass (6.67%), gastroesophageal cancer (6.67%), esophageal varices (6.67%), Dieulafoy's lesion (6.67%), and granularity, friability, loss of vascular pattern secondary to Mycobacterium Avium-Intracellulare infection (6.67%).
5. Conclusions 4. Discussion
FIT is an easy test to administer. It has significantly higher concordance than that expected by chance alone, for both positive and negative gFOBT results in the hospitalized patients. In patients being investigated for GI bleed, FIT can be used as a rule out test, although clinical judgement will be required to address potential false positives. There’s a high degree of agreement in results between days 1 and 3 of gFOBT, indicating that waiting for three days before analysis is not necessary for the higher sensitivity Hemoccult Sensa, especially in the inpatient setting.
gFOBT is used as a test for colorectal cancer screening and is designed to pick up occult bleeding in outpatient/ambulatory setting. FIT has been a later development to gFOBT and has been shown to have good performance in CRC screening [3,19]. While there’s abundance evidence for the clinical utility of both gFOBT and FIT in CRC screening, there’s lack of such in support of its use in symptomatic patients [17,21–24]. Consequently, no clinical guidelines exist to address clinical utility of gFOBT and FIT in symptomatic/hospitalized patients [21]. Recent studies suggest use of FIT in community/ambulatory setting in patients presenting with symptoms can aid in the rule out of disorders such as CRC and IBD [12,22]. Our study found a high concordance between the gFOBT between
Acknowledgements This study was funded by the Winnipeg Health Sciences Centre Foundation. The authors would like to thank the Research Studies 4
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Table 5 Comparison of indications for FOBT order and corresponding test results for Day 1 gFOBT, Day 3 gFOBT, and FIT. Indication
Day 1 gFOBT Results
a
Anemia (lab values) Anemia (patient chart)b Iron Deficiency Non-Bloody Diarrhea CRC Screening Melena/Black Stool Prior to Initiating Anticoagulants Overt GI Bleedingc GI Symptomsd Othere Total
Day 3 gFOBT Results
FIT Results
Pos
Neg
Total
Pos
Neg
Total
Pos
Neg
Total
32 (39.02%) 9 (10.98%) 1 (1.22%) 0 (0.00%) 0 (0.00%) 14 (17.07%) 0 (0.00%) 15 (18.29%) 5 (6.10%) 6 (7.32%) 82 (100%)
63 (34.05%) 25 (13.51%) 4 (2.16%) 15 (8.11%) 5 (2.70%) 16 (8.65%) 0 (0.00%) 29 (15.68%) 22 (11.89%) 6 (3.24%) 185 (100%)
95 (35.58%) 34 (12.73%) 5 (1.87%) 15 (5.62%) 5 (1.87%) 30 (11.24%) 0 (0.00%) 44 (16.48%) 27 (10.11%) 12 (4.49%) 267 (100%)
35 (36.08%) 15 (15.46%) 1 (1.03%) 0 (0.00%) 0 (0.00%) 19 (19.59%) 0 (0.00%) 12 (12.37%) 8 (8.25%) 7 (7.22%) 97 (100%)
83 (34.87%) 34 (14.29%) 4 (1.68%) 18 (7.56%) 5 (2.10%) 22 (9.24%) 1 (0.42%) 34 (14.29%) 31 (13.03%) 6 (2.52%) 238 (100%)
118 (35.22%) 49 (14.63%) 5 (1.49%) 18 (5.37%) 5 (1.49%) 41 (12.24%) 1 (0.30%) 46 (13.73%) 39 (11.64%) 13 (3.88%) 335 (100%)
23 (34.85%) 9 (13.64%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 13 (19.70%) 0 (0.00%) 11 (16.67%) 6 (9.09%) 4 (6.06%) 66 (100%)
91 (35.55%) 36 (14.06%) 5 (1.95%) 18 (7.03%) 5 (1.95%) 25 (9.77%) 1 (0.39%) 34 (13.28%) 32 (12.50%) 9 (3.52%) 256 (100%)
114 (35.40%) 45 (13.98%) 5 (1.55%) 18 (5.59%) 5 (1.55%) 38 (11.80%) 1 (0.31%) 45 (13.98%) 38 (11.80%) 13 (4.04%) 322 (100%)
FIT = Fecal Immunochemical Test. gFOBT = guaiac Fecal Occult Blood Test. between menstrual blood or GI bleed • Differentiate had previous positive gFOBT result but negative FIT result from the same sample − 2 more FOBT samples were sent for FOBT • Patient history of upper GI bleed • Previous blood on peri-anal area • Occasional contained frothy mucus • Stool experienced “red jelly-like” stool • Patient experienced BM with “red flecks” • Patient Newborn experienced ?bloody BM - unsure if bloody stool or blood from the mother during delivery •Includes patients that had hemoglobin values below the normal range within 48 h prior to FOBT sample collection.
a
b c d e
Includes patients that had anemia documented in the progress notes in their chart prior to FOBT sample collection. Includes the following criteria: Coffee ground emesis, Hemeatemesis, Hematochezia, Bright Red Blood Per Rectum Includes the following criteria: Abdominal pain, Diarrhea, Dyspepsia, Heartburn, Nausea/Vomiting Includes:
Table 6 Percent agreement between FOBT results based on indication for FOBT order. Indication
Anemia (lab values)a Anemia (patient chart)b Iron Deficiency Non-Bloody Diarrhea CRC Screening Melena/Black Stool Prior to Initiating Anticoagulants Overt GI Bleedingc GI Symptomsd Othere
FIT and Day 1 gFOBT Results
FIT and Day 3 gFOBT Results
Day 1 and Day 3 gFOBT Results
% Agreement
Expected agreement
P-value
% Agreement
Expected agreement
P-value
% Agreement
Expected agreement
P-value
80.65% 84.38% 80.00% N/A N/A 79.31% N/A
59.56% 66.41% 80.00% N/A N/A 50.77% N/A
< 0.001 < 0.001 N/A N/A N/A < 0.001 N/A
84.21% 86.67% 80.00% N/A N/A 78.95% N/A
61.51% 60.00% 80.00% N/A N/A 50.00% N/A
< 0.001 < 0.001 N/A N/A N/A < 0.001 N/A
91.58% 88.24% 100.00% N/A N/A 96.67% N/A
56.70% 61.07% 68.00% N/A N/A 50.44% N/A
< 0.001 < 0.001 0.01 N/A N/A < 0.001 N/A
86.05% 88.89% 83.33%
57.38% 72.15% 50.00%
< 0.001 < 0.001 0.01
88.89% 89.47% 61.54%
61.93% 69.81% 48.52%
< 0.001 < 0.001 0.15
88.64% 96.30% 75.00%
57.23% 67.49% 50.00%
< 0.001 < 0.001 0.04
N/A - Indicates scenario where percent agreement, expected agreement, or p-value could not be calculated. FIT = Fecal Immunochemical Test. gFOBT = guaiac Fecal Occult Blood Test. a-e See legend of Table 5 for details.
Office and staff of the Health Sciences Centre Laboratory of Shared Health Inc., Manitoba, Canada. [5]
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[19] D. Major, H. Bryant, M. Delaney, S. Fekete, L. Gentile, M. Harrison, V. Mai, E. Nicholson, Y. Taylor, Colorectal cancer screening in Canada: results from the first round of screening for five provincial programs, Curr. Oncol. 20 (2013) 252–257, https://doi.org/10.3747/co.20.1646. [20] P.A. Harris, R. Taylor, R. Thielke, J. Payne, N. Gonzalez, J.G. Conde, Research Electronic Data Capture (REDCap) - a metadata-driven methodology and workflow process for providing translational research informatics support, J. Biomed. Inform. 42 (2009) 377–381, https://doi.org/10.1016/j.jbi.2008.08.010. [21] Canadian Agency for Drugs and Technologies in Health, Urgent, Non-Screening Fecal Occult Blood Testing for Patients with Suspected Gastrointestinal Bleeding, Ottawa, ON, 2017. [22] C.G. Fraser, Faecal immunochemical tests (FIT) in the assessment of patients presenting with lower bowel symptoms: concepts and challenges, Surgeon 16 (2018) 302–308, https://doi.org/10.1016/j.surge.2018.01.004. [23] C.G. Fraser, S.C. Benton, Detection capability of quantitative faecal immunochemical tests for haemoglobin (FIT) and reporting of low faecal haemoglobin concentrations, Clin. Chem. Lab. Med. (2018) 1–6. doi:10.1515/cclm-2018-0464 LK - http://sfx.library.uu.nl/utrecht?sid=EMBASE&issn=14374331&id=doi:10. 1515%2Fcclm-2018-0464&atitle=Detection+capability+of+quantitative +faecal+immunochemical+tests+for+haemoglobin+%28FIT%29+and+reporting+of+low+faecal+haemoglobin+concentrations&stitle=Clin.+Chem. +Lab.+Med.&title=Clinical+Chemistry+and+Laboratory+Medicine&volume=&issue=&spage=&epage=&aulast=Fraser&aufirst=Callum+G.& auinit=C.G.&aufull=Fraser+C.G.&coden=CCLMF&isbn=&pages=-&date=2018 &auinit1=C&auinitm=G. [24] G.P. Young, E.L. Symonds, J.E. Allison, S.R. Cole, @bullet Callum, G. Fraser, S.P. Halloran, E.J. Kuipers, H.E. Seaman, G.P. Young, E.L. Symonds, Á.S.R. Cole, S.R. Cole, J.E. Allison, C.G. Fraser, S.P. Halloran, Á.H.E. Seaman, H.E. Seaman, E.J. Kuipers, Advances in fecal occult blood tests: the FIT revolution, Dig. Dis. Sci. 60 (2015) 609–622. 10.1007/s10620-014-3445-3. [25] S. Mosadeghi, H. Ren, J. Catungal, I. Yen, B. Liu, R.J. Wong, T. Bhuket, Utilization of fecal occult blood test in the acute hospital setting and its impact on clinical management and outcomes, J. Postgrad. Med. 62 (2016) 91–95, https://doi.org/10. 4103/0022-3859.180553.
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Utility of fecal immunochemical test vs guaiac fecal occult blood test for assessment of gastrointestinal bleed in hospitalized patients ⁎
AbdulRazaq Sokoroa,b,d, , Leigh Anne Shafera, Mitchell Darrc, Harminder Singha a
Department of Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada Department of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada c Department of Family Medicine, University of Manitoba, Winnipeg, Manitoba, Canada d Shared Health Diagnostic Services, Winnipeg, Manitoba, Canada b
A R T I C LE I N FO
A B S T R A C T
Keywords: FIT Hospital patients GI bleeding gFOBT Fecal occult blood
Background: Guaiac fecal occult blood testing (gFOBT) is often used “off-label” for gastrointestinal (GI) bleeding. Fecal Immunochemical Test (FIT) is increasingly replacing gFOBT in colorectal cancer screening and may play a role in assessment for significant bowel disease. We examined the concordance of FIT with gFOBT (Hemoccult Sensa II) among inpatients and between day 1 and day 3 gFOBT results. Methods: FIT was performed alongside gFOBT on all inpatient stool sent for occult blood to the Winnipeg Health Sciences Centre laboratory over 1 y. gFOBT was performed on days 1 and 3 post stool collection, while FIT was performed on day 1 only. Results: Positivity rates were highest for Day 1 gFOBT (27.7%), and lowest for FIT (18.3%). Concordance between FIT and Days 1 and 3 gFOBT for negative test results (96.4% and 94.1%) was significantly higher than that expected by chance alone (58.7% and 61.3%, P < .001). Similarly, concordance for positive test results (55.8% and 55.6%) was significantly higher as well as for days 1 and 3 gFOBT results. Conclusions: We found no benefit in delayed testing for 3 days post collection. FIT provides equivalent results to gFOBT in hospitalized patients.
1. Introduction Fecal test for occult blood (FOBT) is used as a screening test for Colorectal Cancer (CRC), which has led to a decrease in incidence and mortality of CRC when used in conjunction with additional testing strategies (such as colonoscopy) [1–3]. However, FOBT is often used “off-label” in the inpatient setting to detect the presence or absence of a gastrointestinal (GI) bleed in symptomatic patients [4,5]. In this case, FOBT is used to assist clinical judgement, in order to determine whether additional diagnostic testing/interventions (such as gastrointestinal endoscopy) should be performed or not. There is an increasing interest in the use of the fecal immunochemical test (FIT) to triage patients with gastrointestinal symptoms. However, the criteria used for FOBT in the outpatient screening setting may not be suitable for the inpatient or symptomatic populations, as these populations often require both emergency ordering of the test, and rapid test results [5–9]. As it stands, the current standards for FOBT in place in many laboratories may not meet these criteria. There are many types of FOBT on the market. Hospital laboratories
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in many jurisdictions, currently employ the guaiac FOBT (gFOBT; Hemocult II Sensa, Beckman Coulter, Inc.), which detects the peroxidase-like activity of heme within stool [2,10]. However, this property is also present in non-human sources of hemoglobin as well as plant peroxidases, which can lead to false positive test results [10]. As such, the gFOBT requires that the patient undergoes dietary restriction of foods containing these factors (such as red meats, and certain raw fruits and vegetables) for 3 days prior to stool specimen collection. As an extra precaution or alternatively, development of the gFOBT is held for 3 days after arrival at the laboratory, to allow for degradation of the plant peroxidases and to ensure adequate natural dehydration/drying of the stool sample as wet mounts could produce false positive results. In addition, certain medications have been shown to interfere with the gFOBT, such as high doses of vitamin C, which can lead to a false negative test result [11]. Also, as occult GI bleeding (such as bleeding due to CRC) may be intermittent, the sensitivity of an individual gFOBT is relatively poor. As a result, the gFOBT requires multiple sampling (3 stool specimens over 3 consecutive days) to improve sensitivity. However, multiple sampling, patient dietary and medication restriction, and
Corresponding author at: 1502 – 155 Carlton Street, Winnipeg, MB R3C 3H8, Canada. E-mail address: [email protected] (A. Sokoro).
https://doi.org/10.1016/j.cca.2019.10.017 Received 30 July 2019; Received in revised form 29 September 2019; Accepted 18 October 2019 0009-8981/ © 2019 Elsevier B.V. All rights reserved.
Please cite this article as: AbdulRazaq Sokoro, et al., Clinica Chimica Acta, https://doi.org/10.1016/j.cca.2019.10.017
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2.2. Data analysis
time lag until test result availability reduce the utility of gFOBT in the inpatient setting. Previous studies have indeed suggested overall limited utility of positive gFOBT in inpatient settings [5,12–14]. However individual clinicians continue to find it useful for ruling out the presence of active GI bleeding [15], which maybe particularly useful when the presence or absence of GI bleeding cannot be determined otherwise (e.g black stools and increased plasma urea, for which there could be other etiologies and therefore the presence of GI bleeding is uncertain). There are no data on correlation between day 1 and day 3 gFOBT results in the inpatient setting and most laboratories do not provide gFOBT results on the day the test is ordered. There are no data on correlation between day 1 and day 3 Hemoccult Sensa gFOBT results. The Fecal Immunochemical Test (FIT) is a relatively new version of FOBT. FIT uses antibodies specific for human-globin chain content in stool, and therefore is less likely to be affected by plant peroxidases, non-human sources of hemoglobin, and medications [2,4,16]. FIT has been found to have greater sensitivity than gFOBT for CRC screening, and therefore does not require multiple sampling to accurately detect GI blood loss [17]. However, FIT is a more expensive assay than gFOBT, and results can be affected by exposure to extremes in temperature. In addition, the utility of FIT in assessing an upper GI bleed has been questioned, as hemoglobin is degraded by stomach acid during its passage along the GI tract [2,18]. Despite these issues, FIT is thought to be of greater utility than gFOBT in the outpatient setting, and has been adopted by CRC screening programs in several jurisdictions [3,19]. In addition, there is increasing interest in using FIT to triage symptomatic patients and avoid low yield colonoscopies. Due to the apparent strengths of FIT over gFOBT (one time sampling, reduced requirement for dietary/medication restriction, reduced time until test result availability) in the outpatient setting, comparability of FIT and gFOBT (or better performance of FIT) for the inpatient population could lead to potential replacement of gFOBT in all settings by FIT.
All study data were collected and managed using REDCap electronic data capture tools hosted at University of Manitoba [20]. Standard descriptive statistical analysis was performed. The positivity rates and concordance between Day 1 gFOBT, Day 3 gFOBT, and FIT results were compared using contingency tables. The percent agreement between each type of FOBT, including the percent agreement based on FOBT result was determined using Cohen's kappa coefficient. In patients that received an endoscopy, only endoscopies performed within 7 days prior to or up to 90 days post stool specimen collection were included in analysis, in order to relate the FOBT results to the endoscopy findings. Patient endoscopies that identified findings considered to be high-risk for gastrointestinal bleeding (such as gastrointestinal malignancy, arteriovenous malformation, inflammatory bowel disease, mass, stricture, ulcer, esophagitis, varices, and active bleeding) were considered positive for further analysis. For patients that submitted multiple stool specimens for fecal occult blood testing, each specimen was compared to the corresponding endoscopy results and included in analysis. As well, patients with multiple endoscopy results were considered to have an overall positive endoscopy result if they contained at least 1 relevant finding. The patient endoscopy data was compared between the Day 1 gFOBT, Day 3 gFOBT, and FIT results using contingency tables. All of the above analyses utilized the manufacturer's recommended value of ≥100 ng hg/ml as the cut-off for a positive FIT outcome. In addition, the outcomes for FIT were evaluated at cut-off concentrations less than or greater than the manufacturer's recommended value using receiver operating characteristic (ROC) analysis. ROC curves were generated by plotting sensitivity against 1-specificity of FIT results, using in patient gFOBT results as a surrogate for a gold standard outcome. The research study was approved by the University of Manitoba Health Research Ethics Board. 3. Results
2. Materials & methods 3.1. Patient demographics and management 2.1. Study design During the study period, 135 patient records were reviewed. One patient record was excluded from analysis, due to the absence of hospital admission, leaving 134 patient records included in analysis. Each patient was unique i.e. only had one hospital admission included in the study. Of all patients included in analysis, 104 patients (77.61%) had 1 stool specimen collection sent for FOBT, 11 patients (8.21%) had 2 stool specimen collections sent for FOBT, 18 patients (13.43%) had 3 stool specimen collections sent for FOBT, and 1 patient (0.75%) had 4 stool specimen collections sent for FOBT throughout the course of their hospital encounter. This yielded 155 Day 1 gFOBT results, 184 Day 3 gFOBT results, and 180 FIT results for analysis. 14 patients (10.45%) did not have any Day 1 gFOBT results available. The patient cohort was 58% male, and patient age on admission ranged from 0 (newborn) − 94.5 years old (median age 49.81). While 21 patients (16%) were found to be NPO status at the time of stool specimen collection, 0 patients (0%) were found to have a diet restriction initiated 72 h prior to at least 1 stool specimen collection for FOBT. Of the patients included in analysis, 28 patients (20.90%) were found to have at least 1 positive FIT result, 39 patients (29.10%) were found to have at least 1 positive Day 1 gFOBT result, and 37 patients (27.61%) were found to have at least 1 positive Day 3 gFOBT result. Of the patients with at least 1 positive FIT result, 7 (25.00%) underwent endoscopy within 7 days prior to or up to 90 days post stool specimen collection.
In order to compare FIT to gFOBT, a commercial quantitative FIT (Eiken Chemical Company Ltd.) was introduced to the Health Sciences Centre (HSC) laboratory. During the study period from February 2014 to February 2015, all inpatient stool specimens sent for occult blood were automatically assigned a FIT assay in addition to the usual gFOBT. For these specimens, the gFOBT was performed alongside FIT on Day 1 (i.e., the day that the specimen was collected). The stool specimen was also applied to a second gFOBT card on Day 1, which was held until development on Day 3, to allow for the natural drying of the stool and degradation of plant peroxidases (as per laboratory protocols). The FIT and Day 3 gFOBT results were then entered into the laboratory information system (LIS) and released to the ordering physician simultaneously after the Day 3 gFOBT results became available. The Day 1 gFOBT results were recorded in a study binder in the laboratory, and were not released to the ordering physician. FIT results were recorded as a numerical value in ng of hemoglobin per ml (ng hg/ml), while gFOBT results were recorded as a qualitative (positive/negative) result. In cases where the FIT result exceeded the manufacturer's recommendation for the upper limit of accurate hemoglobin detection (upper limit of quantitation, > 1000 ng hg/ml), the FIT result was recorded as > 1000 ng hg/ml. A retrospective chart review was performed on patients that had at least 1 FIT and 1 Day 3 gFOBT result available. Study data collected during chart review included: patient demographic information, details and indications related to the FOBT order, patient medication status, patient’s laboratory values prior to FOBT specimen collection, details related to patient management, and patient endoscopy details.
3.2. Positivity and concordance of Day 1 gFOBT, Day 3 gFOBT and FIT Table 1 illustrates the outcomes of the Day 1 gFOBT, Day 3 gFOBT, and FIT assays. Of all the FOBTs performed, 43 of Day 1 gFOBTs were 2
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Table 1 Positivity rates of Day 1 gFOBT, Day 3 gFOBT, and FIT. FIT assay is considered positive for values ≥100 ng hg/ml buffer. Test
Positive Results
Negative Results
Total
Day 1 gFOBT Day 3 gFOBT FIT
43 (27.74%) 45 (24.46%) 33 (18.33%)
112 (72.26%) 139 (75.54%) 147 (81.67%)
155 (100%) 184 (100%) 180 (100%)
Table 3 Comparison of Day 1 gFOBT vs Day 3 gFOBT results. Day 1 gFOBT Result
Positive Negative Total
FIT = Fecal Immunochemical Test. gFOBT = guaiac Fecal Occult Blood Test.
Day 3 gFOBT Result Positivee
Negativef
Total
33 (86.84%) 5 (13.16%) 38 (100%)
10 (8.55%) 107 (91.45%) 117 (100%)
43 (27.74%) 112 (72.26%) 155 (100%)
e ,f Expected agreement among gFOBT positive results is found by multiplying the total percent positive for gFOBT by the total percent positive for FIT. Expected agreement among gFOBT negative results is found by multiplying the total percent negative for gFOBT by the total percent negative for FIT. FIT = Fecal Immunochemical Test. gFOBT = guaiac Fecal Occult Blood Test.
positive (27.74% positivity: [43/155] × 100), 45 of Day 3 gFOBTs were positive (24.46% positivity: [45/184] × 100), 33 of FITs were positive (18.33% positivity: [33/180] × 100). Table 2 shows the concordance between the gFOBT and FIT results. Comparison of FIT and Day 1 gFOBT results show that while the concordance among negative results (96.36%) is larger than that expected by chance (58.7%), the concordance among positive results is more striking. Because a positive test is relatively rare, expected agreement (by chance) is just 5.1%. Actual agreement was 44.19−9-times larger than that expected by chance. Similarly, comparison of FIT and Day 3 gFOBT results show that while the concordance among negative results (94.07%) is larger than that expected by chance (61.3%), the concordance among positive results (55.56%) is over 10-times larger than that expected by chance (4.6%). Table 3 shows comparison of Day 1 and Day 3 gFOBT. Results show high degree of concordance for negative results (91.45%), and positive results (86.84%). Comparing FIT, Day 1 and Day 3 gFOBT, we found that 11% of people tested positive on all three tests. Table 4 illustrates the agreement between the Day 1 gFOBT, Day 3 gFOBT, and FIT results. Agreement between FIT and Day 1 gFOBT was found to be statistically significant at 84.97% (P < .001), agreement between FIT and Day 3 gFOBT was found to be statistically significant at 84.44% (P < .001), and agreement between Day 1 and Day 3 gFOBT was found to be statistically significant at 90.32% (P < .001).
Table 4 Percent agreement between FOBT results. Test
Agreement
Expected Agreement
P-value (Cohen’s kappa)a
FIT vs Day 1 gFOBT FIT vs Day 3 gFOBT Day 1 gFOBT vs Day 3 gFOBT
84.97% 84.44% 90.32%
63.88% 65.83% 61.34%
< 0.001 < 0.001 < 0.001
FIT = Fecal Immunochemical Test. gFOBT = guaiac Fecal Occult Blood Test. a Tests whether the agreement in tests is statistically significantly larger than the agreement expected by chance.
Fig. 1 illustrates the ROC curves of FIT compared to Day 1 and Day 3 gFOBT. The overall agreement between FIT and gFOBT, using all FIT result values as a cut-off for a positive FIT outcome, was greatest between FIT and Day 1 gFOBT (Area under the curve = 0.8358, Fig. 1A), compared to FIT and Day 3 gFOBT (AUC = 0.7824). The individual FIT cut-offs that showed the greatest agreement between FIT and Day 1 gFOBT (85.62% agreement) occurred at values of 98, 137, and 358 ng hg/ml. In contrast, the individual FIT cut-offs that showed the greatest agreement between FIT and Day 3 gFOBT (85.00% agreement) occurred at values of 156, 216, 295, 358, 584 ng hg/ml (Fig. 1B).
chart (14.63%), overt GI bleeding (13.73%), melena/black stool (12.24%), GI symptoms (11.64%), and non-bloody diarrhea (5.57%). Less common indications for ordering of FOBT included iron deficiency (1.49%), CRC screening (1.49%), and FOBT ordering prior to initiating anticoagulants (0.30%). Table 6 indicates the percent agreement between FOBT results based on indications for FOBT ordering. Comparison of FIT and day 1 gFOBT was found to have more agreement than would be expected by chance for the indications of: anemia (by lab values), anemia (by patient chart), melena/black stool, overt GI bleeding, and GI symptoms (P < .001 for each indication). Comparison of FIT and Day 3 gFOBT was found to have more agreement than would be expected by chance for the indications of: anemia (by lab values), anemia (by patient chart), melena/black stool, overt GI bleeding, and GI symptoms (P < .001 for each indication). Comparison of Day 1 and Day 3 gFOBT was also found to have more agreement than would be expected by chance for the indications of: anemia (by lab values), anemia (by patient chart), melena/black stool, overt GI bleed, and GI symptoms (P < .001 for each indication), as well as for the indication of iron deficiency (P < .01).
3.4. Indications for FOBT order and stool specimen collection
3.5. Endoscopy findings
Table 5 illustrates the indications for FOBT ordering. The most common indications for ordering of FOBT included anemia indicated by the patient's most recent hemoglobin lab values within 48 h prior to stool specimen collection (35.22%), anemia documented in the patient
Of all the patients in the study, 20 patients (14.93%) received an endoscopy within 7 days prior to or up to 90 days following stool specimen collection for FOBT. Of these, 2 patients (10.00%) had 2 types of endoscopy performed on the same day. Of the 22 total endoscopies
3.3. Receiver operating characteristics analysis
Table 2 Comparison of FIT results. FIT assay is considered positive for values ≥ 100 ng hg/mL buffer. FIT Result
Day 1 gFOBT Result Positive
Positive Negative Total
a
24 (55.81%) 19 (44.19%) 43 (100%)
Day 3 gFOBT Result Negative
b
4 (3.64%) 106 (96.36%) 110 (100%)
Total
Positivec
Negatived
Total
28 (18.30%) 125 (81.70%) 153 (100%)
25 (55.56%) 20 (44.44%) 45 (100%)
8 (5.93%) 127 (94.07%) 135 (100%)
33 (18.33%) 147 (81.67%) 180 (100%)
a ,b,c,d Expected agreement among gFOBT positive results is found by multiplying the total percent positive for gFOBT by the total percent positive for FIT. For example, expected agreement among gFOBT positive results is: (43/153)*(28/153) = 5.1%. Expected agreement for each of the 4 gFOBT groupings above are: (a) 5.1%, (b) 58.7%, (c) 4.6%, and (d) 61.3%.%. FIT = Fecal Immunochemical Test. gFOBT = guaiac Fecal Occult Blood Test.
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days 1 and Day 3. This suggests that, the three day waiting period may not be necessary even when there is no diet restriction. One potential explanation for this could be the amount of interferents present in inpatients is not significant enough to impact the assay performance. Another potential explanation could be that among a population with a high positive rate of gFOBT, the study population is enriched with those with higher gastrointestinal bleeding, where the waiting time may not be necessary. A third potential explanation is the use of higher sensitivity gFOBT Hemoccult Sensa in our study. Overall, our study results suggest there is no need to hold specimens in the inpatient setting, especially when using Hemoccult Sensa-this should be incorporated into standard operating procedures of the laboratories. We found that gFOBT and FIT show high concordance for both negative and positive results, in comparison to that expected by chance alone. As expected, given that the majority (79% and 72%) of FIT and Day 3 gFOBT test results were negative, there was a higher FIT/gFOBT concordance among negative than positive gFOBT results. Although 94% of negative Day 3 gFOBT results were also FIT negative (94% concordance among gFOBT negative tests), a somewhat smaller percent of FIT negatives were Day 3 gFOBT negative (86% concordance among FIT negative tests). This, nonetheless, suggests that FIT may be suitable for a rule out strategy, which is clinically helpful in the context of black stools and increased plasma urea, when the presence of GI bleeding is uncertain. This finding is consistent with previous studies [12,23]. Increasingly as per discussion with physicians using FOBT in the inpatient setting, FOBT is primarily used as a rule out test in the inpatient setting, where our study suggests FIT could replace the guaiac FOBT. There is some controversy on whether FIT can be used in upper GI bleed [17,24]. We found in our study a statistically significant agreement by FIT for melena, suggesting that that FIT may be suitable for evaluation of upper GI bleeds. In order not to influence physician behaviour (bias towards FIT results), both FIT and Day 3 results were released together on day 3, although FIT results being ready on Day 1. Despite this, most endoscopies were performed before the FOBT results were available indicating that the test was not being used to assist in clinical decisionmaking. Also, many positive gFOBT results were ignored (patients did not receive endoscopy). This indicates that clinical management was not influenced by the test results and is consistent with previous findings [14,15,25]. However, prior studies have not been able to evaluate the role of same day FOBT testing. It will be interesting to see in future studies, if there is greater reliance on the FOBT results, if they are available on the same day as ordered. Our study results should be interpreted in the context of strengths and limitations. This is a relatively large study performed in an usual practice setting and, hence, results are likely generalizable to other hospitals. However, not everyone in the study underwent other gastrointestinal evaluation tests. Therefore, we cannot compare the results of fecal testing with endoscopy findings for all.
A: FIT vs Day 1 gFOBT (AUC=0.8358)
B: FIT vs Day 3 gFOBT (AUC=0.7824) Fig. 1. Receiver operating characteristics plot of FIT results vs gFOBT results.
performed, 9 (40.91%) were considered positive, due to findings that were considered high-risk for GI bleeding. Table 6 illustrates the FOBT results and endoscopy findings for patients with a positive endoscopy result. The most common findings identified in positive endoscopies include: ulcer (33.33%), stricture (13.33%), and esophagitis (13.33%). Less common findings identified in positive endoscopies include: active bleeding (6.67%), mass (6.67%), gastroesophageal cancer (6.67%), esophageal varices (6.67%), Dieulafoy's lesion (6.67%), and granularity, friability, loss of vascular pattern secondary to Mycobacterium Avium-Intracellulare infection (6.67%).
5. Conclusions 4. Discussion
FIT is an easy test to administer. It has significantly higher concordance than that expected by chance alone, for both positive and negative gFOBT results in the hospitalized patients. In patients being investigated for GI bleed, FIT can be used as a rule out test, although clinical judgement will be required to address potential false positives. There’s a high degree of agreement in results between days 1 and 3 of gFOBT, indicating that waiting for three days before analysis is not necessary for the higher sensitivity Hemoccult Sensa, especially in the inpatient setting.
gFOBT is used as a test for colorectal cancer screening and is designed to pick up occult bleeding in outpatient/ambulatory setting. FIT has been a later development to gFOBT and has been shown to have good performance in CRC screening [3,19]. While there’s abundance evidence for the clinical utility of both gFOBT and FIT in CRC screening, there’s lack of such in support of its use in symptomatic patients [17,21–24]. Consequently, no clinical guidelines exist to address clinical utility of gFOBT and FIT in symptomatic/hospitalized patients [21]. Recent studies suggest use of FIT in community/ambulatory setting in patients presenting with symptoms can aid in the rule out of disorders such as CRC and IBD [12,22]. Our study found a high concordance between the gFOBT between
Acknowledgements This study was funded by the Winnipeg Health Sciences Centre Foundation. The authors would like to thank the Research Studies 4
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Table 5 Comparison of indications for FOBT order and corresponding test results for Day 1 gFOBT, Day 3 gFOBT, and FIT. Indication
Day 1 gFOBT Results
a
Anemia (lab values) Anemia (patient chart)b Iron Deficiency Non-Bloody Diarrhea CRC Screening Melena/Black Stool Prior to Initiating Anticoagulants Overt GI Bleedingc GI Symptomsd Othere Total
Day 3 gFOBT Results
FIT Results
Pos
Neg
Total
Pos
Neg
Total
Pos
Neg
Total
32 (39.02%) 9 (10.98%) 1 (1.22%) 0 (0.00%) 0 (0.00%) 14 (17.07%) 0 (0.00%) 15 (18.29%) 5 (6.10%) 6 (7.32%) 82 (100%)
63 (34.05%) 25 (13.51%) 4 (2.16%) 15 (8.11%) 5 (2.70%) 16 (8.65%) 0 (0.00%) 29 (15.68%) 22 (11.89%) 6 (3.24%) 185 (100%)
95 (35.58%) 34 (12.73%) 5 (1.87%) 15 (5.62%) 5 (1.87%) 30 (11.24%) 0 (0.00%) 44 (16.48%) 27 (10.11%) 12 (4.49%) 267 (100%)
35 (36.08%) 15 (15.46%) 1 (1.03%) 0 (0.00%) 0 (0.00%) 19 (19.59%) 0 (0.00%) 12 (12.37%) 8 (8.25%) 7 (7.22%) 97 (100%)
83 (34.87%) 34 (14.29%) 4 (1.68%) 18 (7.56%) 5 (2.10%) 22 (9.24%) 1 (0.42%) 34 (14.29%) 31 (13.03%) 6 (2.52%) 238 (100%)
118 (35.22%) 49 (14.63%) 5 (1.49%) 18 (5.37%) 5 (1.49%) 41 (12.24%) 1 (0.30%) 46 (13.73%) 39 (11.64%) 13 (3.88%) 335 (100%)
23 (34.85%) 9 (13.64%) 0 (0.00%) 0 (0.00%) 0 (0.00%) 13 (19.70%) 0 (0.00%) 11 (16.67%) 6 (9.09%) 4 (6.06%) 66 (100%)
91 (35.55%) 36 (14.06%) 5 (1.95%) 18 (7.03%) 5 (1.95%) 25 (9.77%) 1 (0.39%) 34 (13.28%) 32 (12.50%) 9 (3.52%) 256 (100%)
114 (35.40%) 45 (13.98%) 5 (1.55%) 18 (5.59%) 5 (1.55%) 38 (11.80%) 1 (0.31%) 45 (13.98%) 38 (11.80%) 13 (4.04%) 322 (100%)
FIT = Fecal Immunochemical Test. gFOBT = guaiac Fecal Occult Blood Test. between menstrual blood or GI bleed • Differentiate had previous positive gFOBT result but negative FIT result from the same sample − 2 more FOBT samples were sent for FOBT • Patient history of upper GI bleed • Previous blood on peri-anal area • Occasional contained frothy mucus • Stool experienced “red jelly-like” stool • Patient experienced BM with “red flecks” • Patient Newborn experienced ?bloody BM - unsure if bloody stool or blood from the mother during delivery •Includes patients that had hemoglobin values below the normal range within 48 h prior to FOBT sample collection.
a
b c d e
Includes patients that had anemia documented in the progress notes in their chart prior to FOBT sample collection. Includes the following criteria: Coffee ground emesis, Hemeatemesis, Hematochezia, Bright Red Blood Per Rectum Includes the following criteria: Abdominal pain, Diarrhea, Dyspepsia, Heartburn, Nausea/Vomiting Includes:
Table 6 Percent agreement between FOBT results based on indication for FOBT order. Indication
Anemia (lab values)a Anemia (patient chart)b Iron Deficiency Non-Bloody Diarrhea CRC Screening Melena/Black Stool Prior to Initiating Anticoagulants Overt GI Bleedingc GI Symptomsd Othere
FIT and Day 1 gFOBT Results
FIT and Day 3 gFOBT Results
Day 1 and Day 3 gFOBT Results
% Agreement
Expected agreement
P-value
% Agreement
Expected agreement
P-value
% Agreement
Expected agreement
P-value
80.65% 84.38% 80.00% N/A N/A 79.31% N/A
59.56% 66.41% 80.00% N/A N/A 50.77% N/A
< 0.001 < 0.001 N/A N/A N/A < 0.001 N/A
84.21% 86.67% 80.00% N/A N/A 78.95% N/A
61.51% 60.00% 80.00% N/A N/A 50.00% N/A
< 0.001 < 0.001 N/A N/A N/A < 0.001 N/A
91.58% 88.24% 100.00% N/A N/A 96.67% N/A
56.70% 61.07% 68.00% N/A N/A 50.44% N/A
< 0.001 < 0.001 0.01 N/A N/A < 0.001 N/A
86.05% 88.89% 83.33%
57.38% 72.15% 50.00%
< 0.001 < 0.001 0.01
88.89% 89.47% 61.54%
61.93% 69.81% 48.52%
< 0.001 < 0.001 0.15
88.64% 96.30% 75.00%
57.23% 67.49% 50.00%
< 0.001 < 0.001 0.04
N/A - Indicates scenario where percent agreement, expected agreement, or p-value could not be calculated. FIT = Fecal Immunochemical Test. gFOBT = guaiac Fecal Occult Blood Test. a-e See legend of Table 5 for details.
Office and staff of the Health Sciences Centre Laboratory of Shared Health Inc., Manitoba, Canada. [5]
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