Head-to-head Comparison of Two Fecal Biomarkers to Screen Children for IBD
Condition: Abdominal Pain; Rectal Bloodloss; Diarrhea; Inflammatory Bowel Disease; Crohn's Disease; Ulcerative Colitis; Irritable Bowel Syndrome
MeSH terms: Crohn Disease; Inflammatory Bowel Diseases; Irritable Bowel Syndrome; Diarrhea; Abdominal Pain
Study type: Observational [Patient Registry]

Summary: 
      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.
    

Detailed description: 
      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.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        Eligible for inclusion are consecutive children and teenagers who consult their
        pediatrician and have gastro-intestinal symptoms suggestive of IBD. Participating centers
        are located in the Northern and Southern region of the Netherlands and the Flemish-speaking
        region of Belgium.
      
Biospecimen description: 
      Feces
    
Keywords: Diagnostic accuracy; Fecal biomarker; Clinical Decision Rule; Cohort Study