Head-to-head Comparison of Two Fecal Biomarkers to Screen Children for IBD
Head-to-head Comparison of Two Fecal Biomarkers to Screen Children for IBD
RATIONALE:

 A substantial proportion of children and teenagers with suspected inflammatory bowel disease
 (IBD) referred for endoscopy do not have the disease. The investigators designed a clinical
 decision rule that included a calprotectin stool test to discern which patients require
 further investigations. The accuracy of this diagnostic strategy is 88.5% with a low risk of
 missing IBD cases. Although the number of negative endoscopies was reduced after introduction
 of this strategy, still 22% of the referred children and teenagers underwent an unnecessary
 invasive test. S100A12 (calgranulin C) is a cytoplasmic protein secreted exclusively by
 activated neutrophils and this stool marker may be more IBD-specific than calprotectin.

 OBJECTIVE:

 To determine whether the specificity of S100A12 is superior to the specificity of
 calprotectin without sacrificing sensitivity

 HYPOTHESIS:

 Inclusion of the calgranulin C stool test will improve the specificity of the
 screening-strategy.
DESIGN:

 A prospective diagnostic accuracy study in several outpatient clinics for general paediatrics
 and several tertiary care hospitals in the Netherlands and Belgium.

 STUDY POPULATION:

 Eligible for inclusion are consecutive children and teenagers between 6 and 18 years who
 consult their pediatrician and have gastro-intestinal symptoms suggestive of IBD.

 INTERVENTION:

 Patients will be managed according to a calprotectin-based-referral strategy. Those with an
 elevated calprotectin level without colon pathogens are considered to have a high probability
 of IBD and may require referral for endoscopy (the preferred reference standard). Patients
 with confirmed gastrointestinal infection are advised to have their stools retested. Patients
 with normal calprotectin levels are considered to have a low probability of IBD and will
 therefore have a low change to be subjected to endoscopy. In these patients with low
 probablity of IBD an alternative reference standard may be performed, being clinical
 follow-up for 6 months. The decision for endoscopy or clinical follow up is up to the
 clinician's discretion, based on the combination of all symptoms, physical examination, blood
 results, fecal markers and colon pathogens.

 Next to calprotectin, also S100A12 will be measured in all stool samples. We will perform a
 post hoc scenario analysis to compare the test characteristics of both fecal markers.

 OUTCOME MEASURES:

 The primary outcome measure is the difference in specificity between FC and S100A12 among the
 total number of non-IBD patients.

 We adjusted our previously formulated outcome measure, being the proportion of patients with
 non-inflammatory conditions among the total number of patient subjected to endoscopy, for two
 reasons.

 1. During an interim analysis in August 2016 the proportion of patients subjected to
 endoscopy was lower as expected (34% instead 46%). To reach the required amount of
 patients with the reference standard (endoscopy) we needed to extend the study for
 several months.

 2. Triggered by a recently published paper by Naaktgeboren et al in the BMJ, we realized
 that our initial design would lead to biased results.

 Secondary endpoints are the difference in sensitivity among the total number of patients with
 IBD and the diagnostic accuracy characteristics (sensitivity, specificity, positive
 predictive value, negative predictive value, area under the curve, best cut-off point) for
 both markers individually. All diagnostic accuracy characteristics will be calculated with 1)
 a pre-specified cut-off value based on literature, 2) the best cut-off point calculated with
 the data from this trial.

 POWER/DATA ANALYSIS:

 At the start of our trial we defined a sample size calculation, based on the previously
 described outcome measure including only patients with endoscopy. Based on a previous cohort
 study we expected that 46% of the recruited patients would undergo endoscopy. Using a sample
 size calculation based on independent samples calculated with a Fisher's exact test, we
 calculated that with 154 patients subjected to endoscopy the study would have 80% power to
 detect a 50% relative reduction of the primary outcome from 22% false positives with FC to
 11% false positives with S100A12, at a one-sided alpha level of 0.05. The total number of
 patients to be recruited for this diagnostic accuracy study was therefore calculated at 335.

 In the slipstream of the adjustment of the primary outcome measure, we adjusted our sample
 size. We now use McNemar's test for paired samples to compare the proportion of concordant
 and discordant results between FC and S100A12 in all patients with the disease or without the
 disease.

 To calculate the new sample size we used a specificity of FC of 0.70, based on recent
 individual patient data meta-analysis of Degraeuwe and we expected S100A12 would lead to 50%
 relative improvement. A sample size of 130 subjects achieves 80% power to detect a difference
 of 0,15 between the two diagnostic tests whose specificities are 0,70 and 0,85. This
 procedure uses a two-sided McNemar test with a significance level of 0,05. The prevalence of
 non-IBD in the population is 0,64. The proportion of discordant pairs is 0,23.

 ETHICAL CONSIDERATIONS:

 The Medical Ethical Committee of the University Medical Center in Groningen has granted
 exemption from WMO-approval, as it involves the collection of data generated by routine
 medical care. After measurement of calprotectin levels and testing for microbial gut
 pathogens the residual material will be used for the measurement of calgranulin C levels.
 When patients and their parents give permission, residual feces will be stored for a maximum
 period of 15 years for future diagnostic research.

 TIME SCHEDULE:

 Total running time is 30 months, including 6 months to complete the follow up and 2 months
 for analysis and reporting.
Eligible patients are those aged between 6 and 18 years with at least one of the following
 criteria:

 -  Persistent diarrhea (at least 4 wks)

 -  Recurrent abdominal pain with diarrhea (at least 2 episodes in 6 months)

 -  Rectal bloodloss

 -  Peri-anal disease

 OR at least two of the following criteria:

 -  Involuntary weight loss

 -  First degree family member with IBD

 -  Anemia (HB < -2 SD for age and gender)

 -  Increased marker of inflammation (ESR >20 mm/hour or CRP >10 mg/L)

 -  Extra-intestinal symptoms (erythema nodosum, arthritis, uveitis, thromboembolism,
 aphtous ulcera)

 We did not define any exclusion criteria.