Articles were obtained from the electronic databases PubMed, Embase and Cochrane, without restrictions with respect to the publication date and language. Lists of synonyms for CT-colonography were produced (Fig. 1) and combined using the Boolean operator “OR”. The same was done for colonoscopy. Both search results were combined, using the Boolean operator “AND”. By reading title and abstract of all retrieved articles, two observers identified possible relevant papers, based on the inclusion and exclusion criteria described below. The remaining articles were retrieved as full-text articles and independently checked by two reviewers. Disagreement regarding inclusion was resolved by consensus. Reference lists of the final selection of articles were checked manually to identify other relevant papers. If additional information of an article considered for inclusion was needed due to incomplete data or description of the methods, the corresponding authors were contacted.

Inclusion criteria were prospective, randomized trials or cohort studies, in humans ≥50 years, in which at least 50 predominantly asymptomatic average risk subjects (≥95%) underwent CT-colonography and completed colonoscopy for verification within 3 months. In addition, eligible studies needed to report the detection of colorectal polyps (adenomatous and non-adenomatous), advanced neoplasia and CRC and should include true-positive (TP), false-positive (FP), true-negative (TN) and false-negative (FN) values. Studies that included predominantly high risk subjects (symptomatic, history of hereditary CRC, personal history of polyps, CRC or IBD) were excluded, as well as studies that performed CT-colonography as a consequence of incomplete colonoscopy or studies that only performed colonoscopy after positive findings on CT-colonography.

Systematic assessment of quality and documentation of relevant data of the selected articles was performed independently by two reviewers, using a standardized form. To grade the study quality, the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool was used with special focus on the characteristics of the included study population, index test and reference test [¹²]. We assessed whether the inclusion and exclusion criteria were described clearly and would result in a representative screening cohort. In addition,the presence of a disease progression bias and a verification bias was determined: did all participants receive their reference test <3 months? Furthermore, we assessed whether the index test did not form part of the reference standard, whether all subjects received the same reference test, if the test results of both test were interpreted without knowledge of the other test results and whether withdrawals or uninterpretable test results were reported. Results are presented in Appendix 1.

The following patient characteristics were documented: number of asymptomatic and symptomatic subjects, sex ratio, mean or median age with age range and CT-colonography indication.

The following characteristics were documented regarding the imaging features of CT-colonography: bowel preparation, dietary restrictions, tagging and bowel distention, use of spasmolytical drugs and type of CT-system and CT-parameters, the positioning of the patient and the use of intravenous contrast medium during CT-colonography. For colonoscopy, the type of bowel preparation and dietary restrictions were documented.

The following characteristics were documented regarding image analysis of both CT-colonography and colonoscopy: number of diagnostic examinations, number and experience of CT-colonography readers and endoscopists, reading strategy on CT-colonography, use of segmental unblinding or second look colonoscopy, determination of size on CT-colonography and during colonoscopy and histopathological confirmation.

For the analysis per patient, 2 × 2 contingency tables were constructed to be able to calculate the sensitivity and specificity values for the following type of lesions: all polyps, adenomatous polyps, advanced adenomas (defined as an adenoma with >25% villous features, size ≥10 mm and/or high grade dysplasia [¹³]), advanced neoplasia and CRC. For each type of lesion, except for CRC, data were collected using the following thresholds: 6–9 mm, ≥6 mm and ≥10 mm, based on the associated potential CRC risk [¹⁴–¹⁶].

For the analysis per polyp, we extracted TP and FN findings to calculate the sensitivity of all polyps, (advanced) adenomas and advanced neoplasia for the same thresholds.

If needed, a request for additional data was send to the corresponding author. If possible, the following matching algorithm was used: the lesion should be at least <50% margin of error in size and should be found in the same or adjacent segment.

Heterogeneity of sensitivity or specificity was assessed using I² statistics [¹⁷]. If I² values were >25%, we considered these data significantly heterogeneous, and random-effects analyses were performed. In case of I^2-values <25%, fixed-effects approaches were used.

For the per-patient analyses, we used bivariate models [¹⁸] to obtain summary estimates of sensitivity and specificity with 95% confidence intervals. For the per-polyp analyses, we used univariate models to obtain summary estimates of sensitivity with 95% confidence intervals. All analyses were performed using SAS software (SAS 9.2 procNlmixed, SAS Institute, Cary, NC, USA).

Publication bias was examined by constructing funnel plots.

Per patient The x-axis consisted of the natural logarithm of the diagnostic odds ratio [\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$ \left( { = \left( {{\hbox{TP}} \times {\hbox{TN}}} \right)/\left( {{\hbox{FN}} \times {\hbox{FP}}} \right)} \right) $$\end{document}] . On the y-axis, we plotted the number of patients.

Per-lesion The x-axis consisted of the sensitivity and on the y-axis, we plotted the number of patients.Egger’s regression tests were used to examine the asymmetry of the funnel plots. A significant regression coefficient (P < 0.05) indicates an association between sample size and the diagnostic values.

Patient characteristics are outlined in Table 1. We included five studies with in total 4,086 patients (54% male). Four studies [²⁶–²⁸, ³⁰, ³¹] did have a study population of over 200 average risk subjects, the largest population comprised 2,249 average risk subjects [²⁷]. The smallest study had a population of 68 participants at average risk [²⁹]. All studies provided a clear description of patient characteristics and the inclusion and exclusion criteria. Three studies included high risk subjects: 2.6% [³⁰, ³¹], 5.2% [²⁸] and 11.3% [²⁷], respectively. The corresponding authors of these papers were contacted to obtain data concerning average risk patients only. This succeeded in two out of three studies, resulting in a total of four datasets containing data of average risk subjects only [²⁶–²⁹] and one study including 2.6% high risk participants [³⁰, ³¹]. Resulting in a total of 4,086 participants, of which 37 were at high risk (0.9%). The mean age varied between 55 and 60.5 years, the minimal age was 50 in four studies [²⁶–²⁹].

Bowel preparation and CT-colonography procedure are outlined in Appendix 2.

Three studies used an extensive bowel preparation predominantly based on 4 liters polyethylene glycol [²⁶–²⁸] combined with a clear liquid diet [²⁶], a low-residue diet [²⁸] or dietary restrictions depending on the institutional standard of the clinical centres where the examinations were done [²⁷]. The remaining two studies both used a more limited preparation based on sodium phosphate [²⁹–³¹]. One study combined this with a clear liquid diet [³⁰, ³¹], the dietary restrictions of the other study were not specified [²⁹].

Three studies used oral tagging [²⁶, ²⁷, ³⁰, ³¹], one study did use intravenous contrast medium [²⁸]. Of one study it was not specified whether the participants received tagging [²⁹]. Bowel preparation was the same for colonoscopy, as both colonoscopy and CT-colonography were performed on the same day in all studies.

Bowel distension methods varied between the studies. Two studies used (primarily) automated CO₂ insufflation, combined with butylscopolamine bromide (Buscopan, Boehringer, Ingelheim, Germany) [²⁶] or glucagonhydrochloride (GlucaGen, Novo Nordisk A’S, Bagsvaerd, Denmark) as spasmolytical drug [²⁷]. Three studies used manual room air [²⁸–³¹]. In one study no spasmolytical drug was administered [²⁸], it was not specified whether spasmolytical drugs were used in the remaining two studies [²⁹–³¹]. Two studies used at least 4 slice CT equipment [²⁹–³¹], two studies used at least 16 slice CT [²⁷, ²⁸] and one study used 64 slice CT [²⁶].

Study characteristics are outlined in Appendix 3. All participants received CT-colonography and colonoscopy on the same day. Different reference standards were used. One study used the colonoscopy results without knowledge of the CT-colonography findings [²⁹], two studies used the colonoscopy result after segmental unblinding as reference [²⁶, ³⁰, ³¹], one study used colonoscopy (followed by a second look colonoscopy if lesions ≥10 mm reported on CTC were missed on the initial colonoscopy) combined with histopathology as reference [²⁷] and another study used the histopathology results of the polyps that were removed during colonoscopy after segmental unblinding [²⁸]. It is unclear whether there were any withdrawals in the selected studies. Uninterpretable results of CT-colonography or colonoscopy (outlined in Table 1) were reported and excluded from the analyses in two studies [²⁶, ³⁰, ³¹].

The characteristics of the readers and the reading strategy are outlined in Appendix 3. The minimal experience of the CT-colonography readers was specified in four out of five studies, and varied between 25 and 100 examinations [²⁶–²⁸, ³⁰, ³¹]. In one study the only reader had 5 years of reading experience [²⁹]. Two studies used 2D read as primary reading strategy [²⁸, ²⁹], two studies used 3D read [²⁶, ³⁰, ³¹] and one study used both reading strategies at random [²⁷]. None of the included studies specified whether CAD was used. The experience of the endoscopists and use of different scopes of the included studies was not specified in most studies [²⁷, ²⁹–³¹]. One study had been done by gastroenterologists with a minimum experience of 1,000 colonoscopies [²⁶], while the gastroenterologists in another study had a prior experience of 3,000 colonoscopies [²⁸].

Size measurement of the polyp was done by the use of an open biopsy forceps [²⁶, ²⁸, ²⁹], by a calibrated linear probe [³⁰, ³¹] or determined by the pathologist [²⁷]. In all studies histopathology confirmation was available.

Four studies used a matching algorithm almost the same as the one described in the methods [²⁶, ²⁸–³¹]. These studies considered a CT-colonography finding to correspond with a colonoscopy lesion, if it was found in the same or adjacent segment. In addition it should be at least <50% margin of error in size [²⁸], in the same or adjacent size category [²⁶, ³⁰, ³¹] or should have a size difference of <4 mm [²⁹] to be considered as a true positive. The fifth study [²⁷] used a different matching algorithm: one or more lesions should be in the same size category, irrespective of location. Of this study new data were requested and received, using the matching algorithm as specified in the methods section.

Per patient data for each of the different size categories regarding all polyps and adenomas respectively, could be obtained in three respectively four of the five studies (Table 2). Per polyp data for each of the different size categories regarding all polyps could be obtained in all studies while per polyp data for adenomas could be obtained in four studies and per polyp data of advanced adenomas and CRC in three of the five studies (Table 3).

Corresponding I² values for heterogeneity are reported in Tables 2 and 3. The results of individual studies are shown in forest plots (Figs. 2 and 3).

All polyps Estimated sensitivities for polyps ≥ 6 mm and ≥ 10 mm (regardless of histology) were 75.9% (95%CI 62.3–85.8) and 83.3% (95%CI 76.8–89.0), while corresponding specificities were 94.6% (95%CI 90.4–97.0) and 98.7% (95%CI 97.6–99.3).

Adenomas Estimated sensitivities for adenomas ≥ 6 mm and ≥ 10 mm were 82.9% (95%CI 73.6–89.4) and 87.9% (95%CI 82.1–92.0), while corresponding specificities were 91.4% (95%CI 84.1–95.5) and 97.6% (95%CI 95.0–98.9).Estimated sensitivities of all polyps and adenomatous polyps of 6–9 mm are available in Table 2.

Advanced adenomas, CRC and advanced neoplasia Estimated results for the detection of advanced adenomas, advanced neoplasia and CRC were not calculated, as a consequence of the small number of participants with these findings (Table 2).

All polyps Estimated sensitivities for polyps ≥ 6 mm and ≥10 mm (regardless of histology), were 74.3% (95%CI 61.6–83.3) and 83.7% (95%CI 76.6–89.0).

Adenomas Estimated sensitivities for adenomas ≥ 6 mm and ≥ 10 mm were 80.0% (95%CI 66.9–88.7) and 85.9% (95%CI 80.4–90.0).

Advanced adenomas Estimated sensitivities for advanced adenomas ≥ 6 mm and ≥10 mm were 83.9% (95%CI 77.6–88.7) and 83.3% (95%CI 77.1–88.8). Estimated sensitivities for polyps and (advanced) adenomas of 6–9 mm, are presented in Table 3.

Advanced neoplasia and CRC Estimated sensitivities for advanced neoplasia and CRC by CT-colonography were not calculated, as a consequence of the small number of CRCs (n = 6) that were detected in the included studies. In all studies, no CRCs were missed (Table 3).

The data points in the funnel plots are symmetrically distributed in a funnel shape suggesting the absence of publication bias (Appendix 4a–5b). In addition, the Egger’s regression tests showed no associations between sample size and diagnostic values (data not shown).

^aasymptomatic=free of symptoms of colonic diseases such as melena, haematochezia, diarrhoea, relevant changes in stool frequency or abdominal pain

^basymptomatic=no melena, anemia or hematochezia more than ones last 6 months, no lower abdominal pain

^casymptomatic=no significant GI signs or melena, hematochezia, iron-deficiency anemia, weight loss or abdominal pain within 6 months before study

^dasymptomatic=no iron deficiency anemia last 6 months, no melena or hematochezia last 12 months, no unintentional weight loss >10 lb (4.5 kg) last 12 months

^aIf I² values of sensitivity and/or specificity were larger than 25%, data were considered as significantly heterogeneous

^bNo lesions <6 mm found

^cNot possible to calculate estimated sensitivity and specificity due to small numbers, data regarding TP, FP, FN and TN values not available

^aIf I² values of sensitivity and/or specificity were larger than 25%, data were considered as significantly heterogeneous

¹Defined as <3 months.

²Reference standard=colonoscopy after segmental unblinding or second look colonoscopy

³Reference standard=colonoscopy followed by a second look colonoscopy if there was no match for polyps >9 mm on CT-colonography

⁴Of the 2,600 subjects recruited, 69 subjects were excluded in the analysis as a consequence of incomplete colonoscopy and/or CT-colonography results, not further specified.

⁵In none of the studies was explained whether there were any withdrawals from the study.