Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Yamamoto, 2015

AP&T

Type of study: prospective single-center study

Setting: Yokkaichi Hazu Medical Centre.

Country: Japan

Conflicts of interest: not reported

Inclusion criteria: Age 18-75yr, endoscopic en histologic diagnosis of UC, the severity of the current exacerbation was mildly or moderately active UC, obvious blood in the stool at entry, active endoscopic inflammation limited to the rectum at entry.

Exclusion criteria: (i) patients who had received sal- azosulfapyridine suppository, mesalazine enema (oral, intravenous, intramuscular or rectal) corticosteroids, im- munosuppressants (including tacrolimus, azathioprine, mercaptopurine) or tumour necrosis factor (TNF)-a blocking agents for the current exacerbation; (ii) had received nonsteroidal anti-inflammatory drugs, anti-diar- rhoeal (loperamide or codeine) or anti-spasmodic medi- cations prior to entry; and (iii) active endoscopic inflammation in the colon above the rectum at entry.

N=180 (Eighty (68%) of the 118 patients with remission continued the treatment (30 with decreased frequency of suppository administration).

Median age, range: 35 (18-74)yrs

Sex: 94 M / 66 F

Other important characteristics:

Describe index test: FCP measurement performed at clinical visits, every 8 weeks during the treatment with mesalazine suppositories. FCP was measured by a quantitative enzyme immunoassay (Human Calpro- tectin Enzyme-linked immunosorbent assay Kit; Cell Sci- ences Inc., Canton, MA, USA).

Cut-off point(s): 55 ug/g

Comparator test: Clinical activity score every 2 months (UC-DAI or PGA); CRP every 2 months.

Cut-off point(s):

Describe reference test: Endoscopic disease activity assessed to the UC-DAI score.

Cut-off point(s): In this study, mildly active disease was defined as 3 ≤ UC-DAI ≤ 5, and moderately active disease as 6 ≤ UC-DAI ≤ 9.

Time between the index test en reference test: not reported.

For how many participants were no complete outcome data available?

N 20 (11%)

Reasons for incomplete outcome data described?

They ceased the suppository treatment during induction therapy, and dropped out of the study.

Outcome measures and effect size (include 95%CI and p-value if available):

The median FCP level significantly decreased at entry versus at week 8, p=0.0003.

The endoscopic scores both at entry and at week 8 significantly correlated with the levels of FCP.

Lasson, 2014

Type of study: prospective RCT

Setting: 5 gastroenterology units

Country: Sweden

Conflicts of interest:

Inclusion criteria: adult patients with UC in clinical remission, but with at least one flare-up during the previous year. The patients were followed for 18 months.

Exclusion criteria: patients on anti-TNF therapy, corticosteroids or NSAIDs, prior colon resection, pregnant patients, comorbid disease.

N=91 (51 interventie, 40 controls)

Prevalence:

Median age (range): 41 (18-69)

Sex: 38 M / 53 F

Other important characteristics:

Describe index test: Stool sampling within 2 weeks of inclusion and thereafter monthly, for 18 months. Determined the FCP concentrations using an enzyme-linked immunosorbent assay (ELISA) (Calprotectin ELISA; Bü̈hlmann Laboratories AG, Basel, Switzerland)

Cut-off point(s): normal when < 50 μg/g , dose escalation when > 300 μg/g twice (when intervention group)

Comparator test: Clinical activity score by Mayo score at baseline.

Cut-off point(s):

Describe reference test: flexible sigmoidoscopy performed within 2 weeks from the inclusion date.

The validated Short Health Scale was assessed.

Relapses were verified by endoscopy in 25 patients (15 in de interventiegroep en 10 in de control groep)

Cut-off point(s):

Time between the index test en reference test: not reported

For how many participants were no complete outcome data available?

N 18

Reasons for incomplete outcome data described? Eighteen patients were excluded (Figure 1). Another patient terminated his participation after the first opvlamming.

Outcome measures and effect size (include 95%CI and p-value if available): There were relapses in 18 (35.3%) and 20 (50.0%) patients in the intervention and the control groups, respectively (p1⁄40.23); and 28 (54.9%) patients in the intervention group and 28 (70.0%) patients in the control group had a FCP> 300 μg/g, of which 8 (28.6%) and 16 (57.1%) relapsed, respectively (p < 0.05)

De Vos, 2013

Type of study: 1-year prospective multicentre open-label longitudinal study

Setting: 17 centers in Belgium and 7 in Norway

Country:

Conflicts of interest:

Inclusion criteria: adult patients with UC in clinical remission under infliximab maintenance therapy (or responding to ifx induction therapy)

Exclusion criteria: cyclosporine treatment in the last months before inclusion, change in immunomodulator dose in the last 4 weeks, evidence of active infection, active tuberculosis, heart failure NYHA class 3-4, colon cancer or dysplasia, and severe or unstable hepatic, gastrointestinal, cardiovascular, respiratory, neurological, psychiatric, haematological, or renal disease.

N= 87 in analyse (total 113)

Prevalence:

Mean age ± SD: 48 ± 15yrs

Sex: 51 M / 62 F

Other important characteristics:

Describe index test: patients provided a single stool sample every 4 weeks. FCP levels were measured using PhiCal enzyme-linked immunoassay kit (Scimedx, Denville, NJ)

Cut-off point(s): 300 ug/g

Comparator test: Clinical activity score using Partial Mayo score and CRP every 2 months or when suspicion of relapses

Cut-off point(s):

Describe reference test: Sigmoidoscopie performed at inclusion and at study end (week 52, except those who required a change in treatment due to relapses.

Cut-off point(s): Mayo endoscopic subcscore (0, normal, 1 mild, 2 moderate, 3 severe).

Time between the index test en reference test: not reported

For how many participants were no complete outcome data available? N 26 (%), but these patients were all excluded

Reasons for incomplete outcome data described?

Insufficient stool samples or missing sigmoidoscopy result at week 52, remaining 87 patients for final analysis.

Outcome measures and effect size (include 95%CI and p-value if available): Main objective: determine whether FCP levels can potentially be used in clinical practice to monitor and/or predict disease activity in patients with UC under infliximab maintenance therapy

Yamamoto, 2015 AM J Gastroent

Type of study: prospective, single-center study

Setting: The Yokkaichi Hazu Medical Center

Country: Japan

Conflicts of interest:

Inclusion criteria: (i) patients who were between 20 and 70 years of age; (ii) patients who were diagnosed with histologi- cally con rmed UC; and (iii) patients who had ileostomy closure following total proctocolectomy and ileal pouch-anal anastomosis for medically refractory UC.

Exclusion criteria: i) patients who developed pouch-related complications (anastomotic leak, pelvic abscess, pouch stula, anastomotic stricture); and (ii) patients who were taking antibiotics, nonsteroidal anti-in amma- tory agents, 5-aminosalicylic acids, corticosteroids, or immunosup- pressive medications within 1 month of the entry to the study.

N=60

Prevalence:

Median age (range): 34 (21–64) years

Sex: 37 M / 23 F

Other important characteristics:

Describe index test: Patients provided a stool sample for the measurement of calpro- tectin and lactoferrin at the clinic visits, every 2 months a er the ileostomy closure. FCP was measured by a quantita- tive enzyme immunoassay (Human Calprotectin enzyme-linked immunosorbent assay Kit, Cell Sciences, Canton, MA).

Cut-off point(s): 56 ug/g

Comparator test: Pouchitis Disease Activity Index (PDAI) assessed every 2 months up to 12 months follow-up after the ileostomy closure.

Cut-off point(s):

Describe reference test: When patients had clinical symptoms suggestive of pouchitis at the clinic visits, endoscopic examination was immediately undertaken. In contrast, all asymptomatic patients underwent endoscopy at the end of this study (12 months a er the ileostomy closure). During the endoscopy, the biopsies were obtained from the ileal pouch in each patient.

Cut-off point(s): Pouchitis was de ned as a PDAI score (maximum score: 18) of ≥7.

Time between the index test en reference test: Not reported

For how many participants were no complete outcome data available?

N (%)

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available): A cutoff value of 56 μg/g for FCP had a sensitivity of 100% and a specificity of 84% to predict pouchitis, whereas a cutoff value of 50 μg/g for lactoferrin had a sensitivity of 90% and a specificity of 86%.

Yamamoto, 2016

Type of study: prospective, single-center study

Setting: The Yokkaichi Hazu Medical Center

Country: Japan

Conflicts of interest:

Inclusion criteria: (1) patients who were between 20 and 70 years of age; (2) patients who had undergone ileocolonic resection and primary anastomosis for active CD; (3) patients in clinical remission (CD activity index (CDAI) score (Best et al. 1976) < 150), who had no endoscopic recur- rence at ileocolonoscopy 6–12 months after sur- gery; and (4) patients who agreed to undergo endoscopic examination during the study period.

Exclusion criteria: (1) patients in whom a defunctioning stoma was created for the protection of ileocolonic anastomosis; (2) patients who had gastroduodenal, jejunal, or proximal ileal disease at the time of surgery; and (3) patients with active colonic or anorectal disease at ileocolonoscopy.

N=30

Prevalence:

Median age (range): 32 (21–48) years

Sex: 17 M / 13 F

Other important characteristics:

Describe index test: FC measurement was performed at clinical visits, every 2 months during the study period.

FCP was measured using a commercially available NS-Prime automatic analyser (Alfresa Pharma Corporation, Osaka, Japan)

Cut-off point(s): 140 ug/g

Comparator test:

Cut-off point(s):

Describe reference test: Endoscopy Baseline, when suspicion of relapses (FCP > 140) or at end of follow-up (when remained asymptomatic)

The endoscopic severity of inflammation in the neoterminal ileum was graded according to Rutgeerts and colleagues (Rutgeerts et al. 1990).

Cut-off point(s): Endoscopic recurrence was defined as a Rutgeerts score ⩾ i2.

Time between the index test en reference test: When the FCP level was elevated (⩾140 μg/g), a second ileocolonoscopy was immediately (within 1 week) undertaken.

For how many participants were no complete outcome data available?

N (%)

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available): The incidence of endoscopic recurrence was significantly higher in patients with elevation of FCP levels versus those with maintained low FCP levels (75% versus 9%). A cut-off value of 140 μg/g for FCP had a sensitivity of 75%, a specificity of 91%, a positive predictive value of 75%, a negative predictive value of 91% and a diagnostic accuracy of 87% to detect endoscopic recurrence.

Zhulina, 2016

Type of study: 24 month prospective study

Setting: outpatient gastroenterology clinic

Country:

Sweden

Conflicts of interest:

Inclusion criteria: patients aged 18 years or older, with a confirmed diagnosis of CD or UC and in clinical remission based on the PGA.

Exclusion criteria: previous substantial surgical resections or any other systemic disease.

N=104 (49CD, 55 UC)

Prevalence:

Median age (IQR): CD opvlamming 50 (42–61), CD remission 58 (41–64) UC opvlamming 56 (38–65)

UC remission 59 (49–65)

Sex: 50 M / 54 F

Other important characteristics:

Describe index test: faecal sample at baseline and every third month until the first relapse or 24-month follow-up.

Cut-off point(s): <250, 250-500, >500 ug/g

Comparator test:

Cut-off point(s):

Describe reference test: Questionnaire which included questions on patient-reported outcome measure (nr of stools/day, abdominal pain, blood and mucus in stool), QOL, …etc.

Cut-off point(s): relapse defined as Increasing symptoms necessitating intensified medical therapy or surgery.

Time between the index test en reference test: not reported

For how many participants were no complete outcome data available?

N 43

Reasons for incomplete outcome data described?

43 patients did not provide a faecal sample on one or more occasions

Outcome measures and effect size (include 95%CI and p-value if available): A doubling of FCP level between two consecutively collected samples was associated with a 101% increased risk of relapse (HR: 2.01; 95% CI: 1.53–2.65; P < 0.001).

Molander, 2015

Type of study: prospective multicentre study

Setting:

Country: Finland

Conflicts of interest:

Inclusion criteria: patients over 18 yrs of age, had established IBD diagnoses, had received anti-TNFa maintenance therapy for at least 11 months and had been in corticosteroid-free remission over the previous 6 months before the inclusion. Maintenance therapy was unaltered during the prospective follow-up after discontinuation of anti-TNFa.

Exclusion criteria: escalation of anti-TNFa during the last 6 months, history of relapse after stopping anti-TNFa, perianal disease with no other effective medication available, severe arthritis as a concomitant indication for TNFa blocking therapy and pregnancy.

N=49 (52 at the start)

Prevalence:16 CD, 33 UC/IBDU

Mean age ± SD: not reported, only age at diagnosis

Sex: 26 M / 23 F

Other important characteristics:

Describe index test: FCP was assayed by immunoassay (CALPRO Calprotectin ELISA Test (ALP); CALPRO AS, Lysaker, Norway)

Cut-off point(s): prior to inclusion all patients had FC < 100ug/g, valued as normal levels.

Comparator test: Clinical activity assessment based on HBI or partial Mayo score

Cut-off point(s):Control visits with clinical activity assessment and stool sampling were performed every 4 weeks up to six months and thereafter every 2 months up to the end of the study. In case of clinical relapse, the patients provided a stool sample for FC measurement.

Describe reference test: All patients underwent an ileocolonoscopy routinely at 4 (n=41/) and 12 months (n=31/34) after the drug withdrawal with biopsies. Endoscopy was not repeated in patients who had undergone the routine follow-up scopy within 2 months prior relapse and the endoscopic disease acitivty had been at least moderate.

Cut-off point(s): endoscopic activity was assessed by the SES-CD or the Mayo-score in UC.

Time between the index test en reference test:

For how many participants were no complete outcome data available?

N 3

Reasons for incomplete outcome data described?

due to lack of follow-up FCP samples.

Outcome measures and effect size (include 95%CI and p-value if available): 15/49 relapsed (31%). The other 69% remained in remission. Patients relapsing showed constantly elevated FCP levels for a median of 94 (13-317) days before the relapse. Significant increase in median FCP levels was seen 2 (p=0.0013) and 6 (p=0.0029) months before endoscopic relapse. Constantly normal FCP concentrations were highly predictive for clinical and endoscopic remission.

Langhorst, 2016

Type of study: single centre trial

Setting: department for internal and Integrative Medicine, Essen-Mitte

Country: Germany

Conflicts of interest:

Inclusion criteria: previous diagnosis of UC, verified by the defining symptoms (rectal bleeding, diarrhoea), endoscopy and histopathology, age > 18yrs and </= 75yrs, inactive UC defined by CAI score </=4

Exclusion criteria: clinically active disease at baseline using CAI, treatment within the previous 3 months with biological therapies or immunosuppressive drugs (azathioprine, methotrexate), infectious or chronic active colitis, relevant somatic comorbidities, pregnancy.

N=91

Prevalence:

Mean age ± SD: 48.1 ± 13.4yrs

Sex: 46 M / 45 F

Other important characteristics:

Describe index test: Blood (WBC and CRP) and faecal samples (FCP, FLA and PMN-e) collected at baseline and at each of the scheduled time points or in the event of an acute flare.

Cut-off point(s): FCP >50ug/g

Comparator test:

Cut-off point(s):

Follow-up for 12 months or until opvlamming.

Describe reference test: CAI was calculated at six predefined time points (baseline, after 1, 3, 6, 9 and 12 months) and in addition when the patient reported symptoms of an acute flare.

Sigmoidoscopy with histology was performed at baseline, in the event of an acute flare when possible, or at the end of the 12-month period, to determine the presence of mucosal inflammation.

Cut-off point(s):

Time between the index test en reference test: not reported

For how many participants were no complete outcome data available?

N (%)

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available): Faecal biomarkers FLA, CAL, and PMN-e were able to distinguish between UC patients with mucosal healing from clinical remission and mild disease, showed significant correlations with endoscopy, and were predictive of a flare.

Jaergui-Amezaga, 2014

Type of study: prospective study

Setting: outpatient clinic of gastroenteroly department at the Hospital Clinic of Barcelona

Country: Spain

Conflicts of interest:

Inclusion criteria: clinically inactive patients with UC assessed by a partial Mayo score </= 1 defined as normal stool frequency or 1 to 2 more stools than normal, no rectal bleeding, and normal PGA during at least 3 consecutive months.

Exclusion criteria: patients who received induction treatment or dose adjustment including oral or topical steroids (any dose) oral mesalamine at doses of 3g/day or higher, rectal 5-ASA acid at doses higher than 3g/week, or anti-TNF within the previous 3 months, patients with severe concomitant diseases, pregnant women.

N=64

Prevalence:

Mean age ± SD: 46 ± 13.6/15.9

Sex: 30 M / 34 F

Other important characteristics:

Describe index test: FC determined at inclusion and every 3 months until the end of the study by a commercial kit (Cerba Internacional, Sabadell, Spain)

Cut-off point(s): 250 μg/g

Comparator test: Clinical activity using Mayo score and classical serum biomarkers (CRP, ESR, leukocytes, platelets, albumin and haemoglobin)

Cut-off point(s):

Describe reference test: High-resolution rectosigmoidoscopy was performed at baseline and at the end of follow-up (52 weeks or relapse).

Cut-off point(s):

Time between the index test en reference test: Not reported

For how many participants were no complete outcome data available?

N 6

Reasons for incomplete outcome data described?

6 patients were lost to follow-up.

Outcome measures and effect size (include 95%CI and p-value if available): The proportion of patients who relapsed was significantly higher in the group of patients with FCP ≥ 250 μg/g (7/14 (50%)) compared with patients with FCP < 250 μg/g (10/49 (20%)), odd ratio=3.9 (95%CI 1.1-13.7)

Ferreiro Inglesias, 2016

Type of study: prospective longitudinal cohort study

Setting: IBD unit of the Department of Gastroenterology of the University Hospital Santiago de Compostela

Country: Spain

Conflicts of interest:

Inclusion criteria: patients aged 18 or older with a previous diagnosis of IBD based on clinical, endoscopic, radiologic, and histologic criteria were considered for inclusion in the study. Patients had to be in clinical remission for at least 6 months on maintenance adalimumab or infliximab therapy.

Exclusion criteria: patients receiving different regimens, any antibiotic or NSAID therapy within the 6 months before inclusion, as well as pregnant, pouchitis, and the presence of any relevant cardiorespiratory, liver, haematological, neurological, renal, or serious psychiatric disorders.

N=95 for final anaylsis (total inclusion of 106)

Prevalence: 71 CD, 24 UC

Mean age, range: 44y (18-78)

Sex: % M / 50.5% F

Other important characteristics:

Describe index test: FCP measurement at inclusion and every 4 months using Bühlmann Quantum Blue reader.

Cut-off point(s): the lower range was 30 to 300 μg/g, the higher rangse covers 30 to 1800 μg/g.

Comparator test: ESR and CRP measurement at inclusion and at 4 month intervals for 1 year or until relapse.

Cut-off point(s):

Describe reference test: Harvey-Bradshaw index or Mayo partial index, assessed at inclusion and at 2 month intervals on the day of ADA or IFX administration up to the end of the study.

Cut-off point(s): relapse in CD was defined as a Harvey-Bradshaw index >4, and in UC as a Mayo partial index >2. End of the study was defined by the diagnosis of relapse or by the end of the 16-month fol- low-up period.

Time between the index test en reference test: not reported

For how many participants were no complete outcome data available?

N 11

Reasons for incomplete outcome data described? Eleven of them were lost over follow-up

Outcome measures and effect size (include 95%CI and p-value if available):

Median FCP concentration at inclusion was significantly higher in IBD patients in whom the disease relapsed at any time over the follow-up (311 μg/g, range 30-1800) than in IBD patients in whom the disease maintained in remission (53 μg/g, range 30-483, p<0.005).

Däbritz, 2013

Type of study: propspective multicentre study

Setting: 4 independent German outpatient clinics specialized in IBD

Country: Germany

Conflicts of interest:

Inclusion criteria: pediatric and adult patients with CD and UC in remission

Exclusion criteria: patients with coexisting cardiopulmonary, hepatic, renal, neurologic, psychiatric and rheumatologic disease, a history of HIV and/or viral hepatitis

N=181 (61 CD, 120 UC), (34 <16yr)

Prevalence:

Median age, range: 37.4yrs (3.5-74.6)

Sex: 82 M / 99 F

Other important characteristics:

Describe index test: Stool concentrations of S100A12 (Calgranulin C) determined by a double-sandwich ELISA.

Cut-off point(s):

Interval between measurements: assessments at three month intervals or when relapse occurred

Comparator test: Fecal calprotectin concentrations determined by ELISA (Immundiagnostik AG, Bensheim, Germany)

Cut-off point(s): 15 μg/g μg/g (= upper limiti normal range)

AND CRP (<4.5mg/L = normal)

Describe reference test: Disease activity determined by disease activity assessment based on the (P)CDAI and the (P)UCAI.

Cut-off point(s): Remission was defined as CDAI < 150, PCDAI < 11, UCAI < 5 and PUCAI <10.

Time between the index test en reference test: not reported

For how many participants were no complete outcome data available?

N not reported

Reasons for incomplete outcome data described? No.

Outcome measures and effect size (include 95%CI and p-value if available): Fecal S100A12 was significantly higher in patients with active CD (1.5 mg/kg; 0.1–175 mg/kg; n 1⁄4 57) compared with patients with CD in remission (0.7 mg/kg; 0.1–97 mg/kg; n 1⁄4 122; P , 0.01)

Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Kolho, 2006

Type of study: prospective cohort study

Setting: pediatric gastroenterology centers at the Helsinki University Central Hospital

Country: Finland

Conflicts of interest:

Study aim: The aim of this study was to assess whether the changes in fecal calprotectin levels reflect therapeutic responss.

In- and exclusion criteria: Fecal specimens were assayed for calprotectin in 57 children undergoing colonoscopy. Among these children, 31 had IBD (UC n /16, Crohn’s disease n /9, indeterminate disease n /6), 13 children had a non-IBD disease, and 13 children had no abnorm- alities as confirmed by macroscopic and histological investigation of the intestine. Fecal calprotectin was prospectively assessed in 15 patients who were prescribed peroral glucocorticoid therapy on clinical grounds.

N=57 of which only 13 were followed up

Prevalence: 31 IBD (16 UC, 9 CD, 6 IBDU)

Mean age, range: 13yrs (4.6-18yrs)

Sex: 8 M / 7 F

Other important characteristics:

Describe index test: Fecal calprotectin was assessed with an enzyme immunoassay (Phical Test; Calpro AS, Oslo) at the start of treatment, at 2 and 4 weeks and thereafter at 4-week intervals until 4 weeks after discontinuation of the steroid.

Cut-off point(s): 100 μg/g for active IBD or 50 μg/g

Comparator test:

Cut-off point(s):

Describe reference test: Endoscopies were performed routinely and biospies were taken.

Blood sampling

Questionnaire concerning clinical symptoms

Cut-off point(s): Histologic findings related to chronic inflammatory bowel disease were graded as mild (chronic inflammatory infiltration, no acute inflammatory infiltration, no or mild architectural disorder), moderate (acute in- flammatory infiltration, mild crypt injury, some crypt abscesses), or severe colitis (excessive crypt injury with crypt abscesses and ulcerations)

Time between the index test en reference test: Fecal specimens were taken at the time of colonoscopy (n /26), within one month (n / 17), or within 3 months (n /14).

For how many participants were no complete outcome data available?

N (%)

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available):

FCP was ≤ 100 μg/g in 70% of the children with normal findings on colonoscopy or a non-IBD disease.

FCP was ≥ 100 μg/g in all but one child with active IBD and in 13/15 of those children who were introduced to glucocorticoids by the clinicians.

FCP values decreased within 4 weeks in line with clinical improvement in 7 children and normalized in 4/15 children during the follow-up. Fecal calprotectin increased in 5/8 of the non-steroid-dependent children after discontinuation of glucocorticoids.

Kolho, 2014

Type of study: prospective cohort study

Setting: children’s Hospital, Helsinki

Country: Finland

Conflicts of interest:

Study aim: long-term prognosis related to the FC value respons to infliximab induction therapy

Inclusion criteria: pediatric patients with IBD entering IFX maintenance therapy

Exclusion criteria: primary nonresponders and patients not providing the requested stool samples.

N=76

Prevalence:

Median age (range): 14.6 (range 6.5–18)

Sex: 44 M

Other important characteristics:

Describe index test: Stool samples for FCP measurement by a quantitative immunoassay (PhiCal Test, Calpro AS, Oslo) scheduled to the timing of the infusion’s administration

Cut-off point(s): values were normal when < 100ug/g

Comparator test: Serum markers of inflammation (ESR and CRP)

Cut-off point(s):

Describe reference test: Clinical disease activity scored with PGA, PUCAI and PCDAI

Cut-off point(s): Clinical disease activity was scored with physician global assessment, PGA (8,24), and with the PUCAI or PCDAI, when appropriate

Time between the index test en reference test: not reported

For how many participants were no complete outcome data available?

N 7

Reasons for incomplete outcome data described?

Patients provided fecal samples only during the baseline and induction period

Outcome measures and effect size (include 95%CI and p-value if available): The median pretreatment FCP level of 817 μg/g stool (range <5–24,000) declined to 372 μg/g (range 5–2430) by week 6, with a low level (<100 μg/g) in 35%. Clinical activity indices showed remission in 59%

Battat, 2017

Type of study: prospective cohort study (cross-sectional and longitudinal)

Setting: the McGill University Health Centre and the Jewish 199

General Hospital, Montreal

Country: Canada

Conflicts of interest:

Inclusion criteria: consecutive adult moderate-to-severe CD patients who were anti-TNF refractory or intolerant

Exclusion criteria:

N=62 (27 longitudinal, 35 cross-sectional)

Prevalence:

Median age (SD): 29.1 (13.6)

Sex: % M / 61.3% F

Other important characteristics:

Describe index test: Baseline, week 2, 10 and week 26 FCP tests were assessed.

Cut-off point(s): 200 ug/g

Interval between measurements: Baseline, week 10 and week 26 clinical outcomes (onder andere FCP) were assessed

Comparator test:

Cut-off point(s):

Describe reference test: Routine endoscopic assessment prior to treatment and after week 26.

Cut-off point(s): using the SED-CD, respons SES-CD

score reduction > 50%.

Time between the index test en reference test: Mean time of endoscopy was 18.4 (±18.4) weeks prior to UST initiation and 30.9 (±9.4) weeks after UST initiation.

For how many participants were no complete outcome data available?

N 6

Reasons for incomplete outcome data described? 5 patients dropped out prior to completion. One patient was lost to follow-up.

Outcome measures and effect size (include 95%CI and p-value if available): The proportion of patients with normal FCP increased from 4.8% (n=21) at baseline to 23.1% at week 26 (n=26; p=0.22)

Burri, 2015

Type of study: Observationalpropespective study

Setting: Department of gastroenterology, university hospital basel

Country: Switzerland

Conflicts of interest:

Inclusion criteria: patients with UC referred for medical treatment to the gastroenterology department

Exclusion criteria: incomplete diagnostic work-up, age younger than 18 years, medical history of primary immunodeficiency, underlying chronic or active malignant disease and current infection, abdominal surgery within 1 month prior to study entry.

N= 41

Prevalence:

Age range: 22-83yrs

Sex: 15 M / 26 F

Other important characteristics:

Describe index test: FC measurement at study entry and consecutively every 2 months using a commercially available enzyme-linked immunosorbent assay (Bühlmann Laboratories, Schönebuch, Switzerland)

Cut-off point(s): FCP ≥ 50 μg/g were considered positive test results.

Interval between measurements: 2 months

Comparator test: Clinical Activity Index (CAI) assessed at study entry and consecutively every 2 months until end of follow-up.

Cut-off point(s):

Describe reference test: Endoscopic assessment by using the Mayo ulcerative endoscopic score, in 26 patients (63.4%) for clinical reason, during the study period, either at inclusion (n=20) or within 3 months thereafter (n=6).

Cut-off point(s):

Time between the index test en reference test: not reported

For how many participants were no complete outcome data available?

N 1

Reasons for incomplete outcome data described?

Only one single fecal sample was provided.

Outcome measures and effect size (include 95%CI and p-value if available): Values of the CAI and FCP correlated with therapy escalation (OR 3.94 and 3.22, respectively). Only for FCP, changes between two measurements were related to intensified medical treatment (OR 1.39).

Lykowska, 2011

Type of study: prospective cohort study

Setting: Department of gastroenterology, Poznan

Country: Poland

Conflicts of interest:

Inclusion criteria: patients with CD who were treated with anti-TNFa were qualified. Good respons to treatment was

Exclusion criteria: pregnancy, fistulas, present stoma, intestinal resections, administration of NSAIDs at least 3 months before qualification for the study. Patients who did not respond to induction treatment were not qualified for the continuation of biological treatment and were therefore excluded.

Disease remission was free from corticosteroids.

N=35 (50 inclusions at baseline, but 15 patients were not in remission/no clinical respons after 3 months induction therapy, they were excluded from analysis)

Prevalence:

Median age, range: 34.5yrs (18-53)

Sex: 42.8% (15) M / 57.1% (20) F

Other important characteristics:

Describe index test: Stool samples were obtained before colonoscopy to measure calprotectin using PhiCal Calprotectin ELISA test (Immunodiagnostik Germany)

Cut-off point(s): unkown

Comparator test: Clinical activity evaluated using CDAI.

Cut-off point(s):

Describe reference test: Every patient underwent a colonoscopy with terminal ileum intubation performed by an experienced endoscopic specialist.

Cut-off point(s): using SES-CD.

Time between the index test en reference test: The three parameters (FCP, CDAI and SES-CD) were performed three times: before admission to the study, after the end of induction treatment (after 3 months – at week 12) and after 12 months of therapy (at week 56)

For how many participants were no complete outcome data available? Not reported.

N (%)

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available): The median FCP before the administration of biological treatment was 178.9 (IQR: 112.3-271.8) mg/ml. After three months the median concentration of FCP was 49.9 (IQR: 11.6-169.6) mg/ml. After a year median FCP was 44.3 (IQR: 11.4-200) mg/ml. The differences were statistically significant P<0.05 when comparing FCP before administration with 12 weeks and with one year treatment, but not between 12 weeks and one year.

Paul, 2013

Type of study: prospective observational study

Setting: Saint-Etienne University Hospital

Country: France

Conflicts of interest:

Inclusion criteria: All adult patients with an established diagnosis of CD or UC for at least 3 months were eligible for inclusion in the study

Exclusion criteria: patients’ refusal to enter the study, exclusive active perianal CD, IFX maintenance regimen at a dose above 5 mg/kg, and primary nonresponders to IFX therapy. Clostridium difficile toxin results were negative in all included patients, and all patients with UC were also negative for cytomegalovirus by PCR on inflamed tissues at the time of inclusion as routinely done in our center.

N= 103

Prevalence:

Mean age ± SD:

Sex: % M / % F

Other important characteristics:

Describe index test: FCP was measured in stools using the Quantum Blue Calprotectin assay (Buhlmann Laboratories, Schonenbuch, Switzerland).

Cut-off point(s): Active disease was defined by a CDAI score > 220 asso- ciated with a C-reactive protein concentration > 10 mg/L and fecal calprotectin level > 450 mg/g stools for patients with CD

Comparator test:

Cut-off point(s):

Describe reference test:

Cut-off point(s): SCCAI >3 associated with an endoscopic Mayo score above 1 for UC and indeterminate colitis patients. A clinical remission was defined by a CDAI <150 for patients with CD and by a SCCAI <3 for both UC and indeterminate colitis patients.

Time between the index test en reference test: not reported

For how many participants were no complete outcome data available?

N (%)

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available): After IFX dose intensification, half of CD and UC patients achieved MH. Increase in IFX trough levels (called “delta IFX” in micrograms per milliliter) was associated with MH in both CD and UC (P 1⁄4 0.001).

Sipponen, 2010

Type of study:

prospective cohort study

Setting: Helsinki University Central Hospital Clinic of Gastroent.

Country: Finland

Conflicts of interest:

Inclusion criteria: CD patients referred for ileocolonoscopy

Exclusion criteria: not reported

N=19

Prevalence:

Median age, range: 31.2yrs (19-51)

Sex:10 M / 9 F

Other important characteristics:

Describe index test: stool samples for FCP measurement three times during the study: at baseline, at a scheduled appointment 2-3months from baseline, and at respons endoscopy (4-6months after baseline endoscopy) by ELISA (PhiCal Test; Calpro AS, Oslo Norway)

Cut-off point(s): < 100 μg/g μg/g is normal.

Comparator test: Clinical acitivity assessed according to the CDAI;

Cut-off point(s): <150 is inactive disease, >150 is active disease. Also CRP measurement at baseline, 2-3 months and 4-6 months.

Describe reference test: Baseline endoscopy (n=17) and 4-6 months after the start of individualized therapy.

Cut-off point(s): Scoring of findings according to SES-CD

Time between the index test en reference test: not reported

For how many participants were no complete outcome data available?

N 2

Reasons for incomplete outcome data described?

One edoscopy remained incomplete due to technical problems and another due to an impassable strictured valvula.

Outcome measures and effect size (include 95%CI and p-value if available): During therapy, both faecal-biomarker concentrations decreased significantly in responders: median FCP from 1282 μg/g (range 156–2277 μg/g) to 73 μg/g (range 7–2222; P = 0.005) and lactoferrin from 233 μg/g (range 2.8–802 mg/g) to 0.0 μg/g (range 0.0–420 μg/g; P = 0.005), and these changes correlated significantly with changes in the SES-CD.

Sipponen, 2008

Type of study: prospective cross-sectional study

Setting:

Country: Finland

Conflicts of interest:

Inclusion criteria: adult patients with established CD and scheduled for ileocolonoscopy, who needed anti-TNFa treatment based on global clinical assessment. After beginning of anit-TNF treatment, corticosteroids were tapered off.

Exclusion criteria: contra-indication to anti-TNFa treatment, pregnancy, history of extensive bowel resection (ileosigmoidesostomy, ileorectostomy), ostomy, long-term use of NSAIDs, or perianal fistulating disease without luminal inflammation.

N=15

Prevalence:

Median age, range: 25 (19-44)

Sex: 60% M / 40% F

Other important characteristics:

Describe index test: Fecal calprotectin was measured at first colonoscopy, and 2, 8 and 12 weeks after the first anti-TNFa treatment. Using PhiCal Test; Calpros, Oslo Norway.

Cut-off point(s): normal values were <100 μg/g in the lab and in the study < 200ug/g, 200-1000 mildly active disease and >1000 severely active disease.

Comparator test: CRP and the CDAI were measured at the same time points as calprotectin

Cut-off point(s): CDAI < 150 indicated clinical inactivity, 150-219 mild, 220-450 moderate, >450 severely active disease.

Describe reference test: ileocolonoscopy scored according to the CDEIS, was performed at beginning of the study and at week 12 (week 10 for adalimumab patients) and during all endoscopies, 4 biospy specimens were taken from the ileum, right, transverse, and left colon, and rectum.

Cut-off point(s):

Time between the index test en reference test: not reported

For how many participants were no complete outcome data available?

N (%)

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available): The median FCP concentration fell from 1173 μg/g to 130 μg/g (P 0.001) Correlation of CDEIS was strong with FCP (r=0.831, p<0.001). In the 5 patients that reached remission with anti-TNFa according to the endoscopy, the fecal calpro concentration declined from 1891 μg/g to 27 μg/g.

Pavlidis, 2016

Type of study: Retrospective cohort study

Setting: Kings College Hospital, Londen

Country: UK

Conflicts of interest:

Inclusion criteria: Anti-TNF-naïve patients with non-penetrating disease who received standard induction with IFX or ADA for active disease based on endoscopic and/or radiologic criteria. Only patients with complete clinical data, including prospectively calculated activity scores, were included (minimum follow-up was 6 months).

N=32

Prevalence:

Median age, range: 33 (18-59)

Sex: f:m 2:1

Other important characteristics:

Describe index test: FCP measurement by BÜhlmann ELISA) pre- and post induction treatment (within one month prior to treatment then 6-8 weeks post first ADA dose, 8-10 weeks post first IFX dose.

Cut-off point(s): 50ug/g

Comparator test: Clinical activity score by HBI and the use of corticosteroids.

CRP results were also collected and analysed at the time point defined for FCP

Cut-off point(s):

Describe reference test: Patients that did not respond had re-evaluation of their disease with either endoscopy or imaging as per attending clinician.

Cut-off point(s):

Time between the index test en reference test: not reported.

For how many participants were no complete outcome data available?

N (%)

Reasons for incomplete outcome data described?

Outcome measures and effect size (include 95%CI and p-value if available): The FCP varied between the three groups with those in remission having the largest drop (remission: -92% ( -85, -95), respons: -80% ( -77, -84), non-respons: -38 ( -250, -2), p<0.0001), while the DCRP did not ( -41% ( -82, 0), -57% ( -91, -9), -43 ( -68, -5), p = 0.70.

Laharie, 2011

Type of study: prospective two-center study

Setting: Gastroenterology departments of Hau-Lévêque and Saint-André Hospitals from Bordaux

Country: France

Conflicts of interest:

Inclusion criteria: CD patients with luminal CD diagnosed at least for 3 months on usual criteria including mucosal ulcers on ileo-colonoscopy and insufficient respons to steroids requiring an IFX induction regimen assoiated with maintenance by an immunosuppressant alone.

Exclusion criteria: Patients with UC, IBDU, contra-indication for IFX or immunosuppressant, surgical resection needed, pure ano-perineal fistulising disease or pregnancy.

N=65

Prevalence:

Median age, range: 30.4 (15-69yrs)

Sex: 66% F

Other important characteristics:

Describe index test:

Calprotectin assay (Calprotectin ELISA; Bühlmann Laboratories AG, Basel, Switzerland), measured at inclusion and at week 14 in patients with remission off steroids.

Cut-off point(s): normal value <50ug/g, furthermore two different cutoff values were studies; 130 μg/g and 250 μg/g, to predict opvlamming.

Comparator test: Laboratory tests including CRP (normal value < 5mg/L)

Cut-off point(s):

Data collection at baseline and at week 14

Describe reference test: CDAI

Cut-off point(s): clinical remission was defined as a CDAI < 150.

Patients with clinical remission off steroids at week 14 were followed for an additional 38 weeks until week 52, with planned visits every three months including physicial examination and routine lab analyses.

Time between the index test en reference test: not reported.

For how many participants were no complete outcome data available?

N 15 (?%)

Reasons for incomplete outcome data described?

No remission at week 14

Outcome measures and effect size (include 95%CI and p-value if available):

Median FCP level at w14 was similar in patients with and without CD clinical relapse (200 and 150 μg⁄g respectively). When considering two suggested FCP cut-offs to predict CD relapse, sensi tivities and specificities were 61% and 48% for 130 μg⁄g, respectively, and 43% and 57% for 250 μg⁄g. Neither FCP nor CRP at baseline and at w14 could predict relapse even when CD location subgroup analysis was considered.

Theede, 2014

Type of study: prospective cohort study

Setting: the Gastrounit, Med- ical Division, Copenhagen University Hospital Hvid- ovre

Country: Denmark

Conflicts of interest:

Inclusion criteria: Patients were identified during admission to the department ward or in the outpatient clinic and included if they were about to begin a high-dose steroid treatment for active UC. The decision to initiate steroid therapy was unrelated to the study protocol and was made by the department’s gastroenterologists.

N= 17

Prevalence:

Median age, range: 35 years (22–66)

Sex: 9 M / 7 F

Other important characteristics:

Describe index test: Stool samples (FC) were collected at days 0, 2, 4, 6, 13, and 27. The stool sample to be analyzed for the concentration of calpro- tectin was collected on the day of treatment initiation but before the first steroid administration. FC was analyzed using a PhiCal ELISA test from CalPro AS.

Cut-off point(s): The assay kit has an upper limit at 3600 mg/kg, so the stool samples were diluted to obtain absolute values of calprotectin above this limit.

Comparator test:

Cut-off point(s):

Describe reference test: Evaluation of the treatment respons was made at day 4–5 (after 3 complete days of steroid treatment) and was based on global physician assessment and retrospectively on decreasing SCCAI score.

Cut-off point(s): Sustained clinical remission was defined as clinical remission from day 27 and during one year and was based on the absence of symptoms and no need for changing treatment modality or dose escalation. Relapse was defined as recurrence of symptoms requiring change of treatment modality or dose esca- lation from day 27 and during one year.

Time between the index test en reference test: not reported

For how many participants were no complete outcome data available?

N 1

Reasons for incomplete outcome data described? biopsies from the colon were compatible with Crohn’s disease.

Outcome measures and effect size (include 95%CI and p-value if available): All patients had significant decreasing levels of FCP (–1014 mg/kg, p = 0.0061), CRP (–10 mmol/l, p = 0.0313), and SCCAI (–3, p = 0.0002) during the first 4 days. After 27 days, the FCP had decreased to 216 mg/kg (p = 0.002).

Study reference

Patient selection

Index test

Reference standard

Flow and timing

Comments with respect to applicability

Kolho 2006

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Unclear

Were the index test results interpreted without knowledge of the results of the reference standard?

Unclear

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

Unclear

Were the reference standard results interpreted without knowledge of the results of the index test?

Yes

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Unclear

Did patients receive the same reference standard?

Unclear

Were all patients included in the analysis?

No

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

Yes

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: UNCLEAR

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: UNCLEAR

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: UNCLEAR

CONCLUSION

Could the patient flow have introduced bias?

RISK: HIGH

Sipponen 2008

Was a consecutive or random sample of patients enrolled?

Unclear

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes/

Were the index test results interpreted without knowledge of the results of the reference standard?

No

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

No

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: HIGH

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Sipponen 2010

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

No

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

No

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: HIGH

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Laharie 2011

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

No

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

No

Were the reference standard results interpreted without knowledge of the results of the index test?

No

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

Yes

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: HIGH

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Lykowska 2011

Was a consecutive or random sample of patients enrolled?

Unclear

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

No

Were the index test results interpreted without knowledge of the results of the reference standard?

No

If a threshold was used, was it pre-specified?

No

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

No

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: HIGH

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Paul 2013

Was a consecutive or random sample of patients enrolled?

Yes

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

No

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Yes

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

No

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: HIGH

Kolho 2014

Was a consecutive or random sample of patients enrolled?

No

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

No

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

No

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: HIGH

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: HIGH

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Theede 2014

Was a consecutive or random sample of patients enrolled?

Unclear

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Unclear

If a threshold was used, was it pre-specified?

No

Is the reference standard likely to correctly classify the target condition?

No

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes/No/Unclear

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

Yes

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: HIGH

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: HIGH

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Burri 2015

Was a consecutive or random sample of patients enrolled?

Unclear

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Yes

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

Unclear

Were the reference standard results interpreted without knowledge of the results of the index test?

Yes

Was there an appropriate interval between index test(s) and reference standard?

Yes

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

No

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW

Plavidis 2016

Was a consecutive or random sample of patients enrolled?

No

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Unclear

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

No

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

No

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

No

Are there concerns that the target condition as defined by the reference standard does not match the review question?

Yes

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: HIGH

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: HIGH

CONCLUSION

Could the patient flow have introduced bias?

RISK: HIGH

Battat 2017

Was a consecutive or random sample of patients enrolled?

Unclear

Was a case-control design avoided?

Yes

Did the study avoid inappropriate exclusions?

Yes

Were the index test results interpreted without knowledge of the results of the reference standard?

Unclear

If a threshold was used, was it pre-specified?

Yes

Is the reference standard likely to correctly classify the target condition?

Yes

Were the reference standard results interpreted without knowledge of the results of the index test?

Unclear

Was there an appropriate interval between index test(s) and reference standard?

Unclear

Did all patients receive a reference standard?

Yes

Did patients receive the same reference standard?

Yes

Were all patients included in the analysis?

Yes

Are there concerns that the included patients do not match the review question?

No

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Yes

Are there concerns that the target condition as defined by the reference standard does not match the review question?

Yes

CONCLUSION:

Could the selection of patients have introduced bias?

RISK: LOW

CONCLUSION:

Could the conduct or interpretation of the index test have introduced bias?

RISK: LOW

CONCLUSION:

Could the reference standard, its conduct, or its interpretation have introduced bias?

RISK: LOW

CONCLUSION

Could the patient flow have introduced bias?

RISK: LOW