Prognostic biomarkers to identify patients likely to develop severe Crohn's disease: a systematic review.

BACKGROUND: Identification of biomarkers that predict severe Crohn's disease is an urgent unmet research need, but existing research is piecemeal and haphazard. OBJECTIVE: To identify biomarkers that are potentially able to predict the development of subsequent severe Crohn's disease. DESIGN: This was a prognostic systematic review with meta-analysis reserved for those potential predictors with sufficient existing research (defined as five or more primary studies). DATA SOURCES: PubMed and EMBASE searched from inception to 1 January 2016, updated to 1 January 2018. REVIEW METHODS: Eligible studies were studies that compared biomarkers in patients who did or did not subsequently develop severe Crohn's disease. We excluded biomarkers that had insufficient research evidence. A clinician and two statisticians independently extracted data relating to predictors, severe disease definitions, event numbers and outcomes, including odds/hazard ratios. We assessed risk of bias. We searched for associations with subsequent severe disease rather than precise estimates of strength. A random-effects meta-analysis was performed separately for odds ratios. RESULTS: In total, 29,950 abstracts yielded just 71 individual studies, reporting 56 non-overlapping cohorts. Five clinical biomarkers (Montreal behaviour, age, disease duration, disease location and smoking), two serological biomarkers (anti-Saccharomyces cerevisiae antibodies and anti-flagellin antibodies) and one genetic biomarker (nucleotide-binding oligomerisation domain-containing protein 2) displayed statistically significant prognostic potential. Overall, the strongest association with subsequent severe disease was identified for Montreal B2 and B3 categories (odds ratio 4.09 and 6.25, respectively). LIMITATIONS: Definitions of severe disease varied widely, and some studies confounded diagnosis and prognosis. Risk of bias was rated as 'high' in 92% of studies overall. Some biomarkers that are used regularly in daily practice, for example C-reactive protein, were studied too infrequently for meta-analysis. CONCLUSIONS: Research for individual biomarkers to predict severe Crohn's disease is scant, heterogeneous and at a high risk of bias. Despite a large amount of potential research, we encountered relatively few biomarkers with data sufficient for meta-analysis, identifying only eight biomarkers with potential predictive capability. FUTURE WORK: We will use existing data sets to develop and then validate a predictive model based on the potential predictors identified by this systematic review. Contingent on the outcome of that research, a prospective external validation may prove clinically desirable. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016029363. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 45. See the NIHR Journals Library website for further project information.

Crohn's disease causes inflammation of the intestines. Traditional treatment uses drugs, such as steroids, at a gradually increasing dose as symptoms worsen. Newer 'biological' drugs may stop disease, but are not used as an early treatment because they are expensive and have serious side effects. Using biologicals early means knowing which patients will develop severe disease in the future. A 'prognostic biomarker' is a measurement made on a patient that predicts a future outcome. A lot of research has attempted to identify biomarkers that predict severe Crohn's disease, but research is haphazard and of variable quality. We therefore carried out a 'systematic review', which identifies research in a comprehensive and unbiased fashion. We found nearly 30,000 research papers, 71 of which were acceptable quality and described 56 groups of Crohn's disease patients. We then used a statistical method called 'meta-analysis' to combine results from multiple studies. This allowed us to identify the most promising biomarkers to predict future severe disease. We found five clinical biomarkers (e.g. age and smoking), two blood biomarkers and one genetic biomarker that seemed reasonably able to predict future severe Crohn's disease. However, we also found that most research was poorly performed and frequently confused diagnosis (current disease) with prognosis (future disease). Some commonly used biomarkers were not sufficiently investigated. We were surprised to identify so few prognostic biomarkers in the face of a seemingly vast amount of research. Future research should be better conducted and not confuse diagnosis with prognosis. We will use statistical methods to combine the promising biomarkers that we identified into a 'prognostic model', which is a mathematical formula that provides the likelihood of developing severe disease in the future. We will then test how well this works by using patient data from existing Crohn's disease databases.

Assessment of the Incremental Benefit of Computer-Aided Detection (CAD) for Interpretation of CT Colonography by Experienced and Inexperienced Readers.

OBJECTIVES: To quantify the incremental benefit of computer-assisted-detection (CAD) for polyps, for inexperienced readers versus experienced readers of CT colonography. METHODS: 10 inexperienced and 16 experienced radiologists interpreted 102 colonography studies unassisted and with CAD utilised in a concurrent paradigm. They indicated any polyps detected on a study sheet. Readers' interpretations were compared against a ground-truth reference standard: 46 studies were normal and 56 had at least one polyp (132 polyps in total). The primary study outcome was the difference in CAD net benefit (a combination of change in sensitivity and change in specificity with CAD, weighted towards sensitivity) for detection of patients with polyps. RESULTS: Inexperienced readers' per-patient sensitivity rose from 39.1% to 53.2% with CAD and specificity fell from 94.1% to 88.0%, both statistically significant. Experienced readers' sensitivity rose from 57.5% to 62.1% and specificity fell from 91.0% to 88.3%, both non-significant. Net benefit with CAD assistance was significant for inexperienced readers but not for experienced readers: 11.2% (95%CI 3.1% to 18.9%) versus 3.2% (95%CI -1.9% to 8.3%) respectively. CONCLUSIONS: Concurrent CAD resulted in a significant net benefit when used by inexperienced readers to identify patients with polyps by CT colonography. The net benefit was nearly four times the magnitude of that observed for experienced readers. Experienced readers did not benefit significantly from concurrent CAD.

Public perceptions and preferences for CT colonography or colonoscopy in colorectal cancer screening.

OBJECTIVES: To examine public perceptions of and preferences for colonoscopy vs. CT colonography (CTC) as technologies for colorectal cancer (CRC) screening. METHODS: Six discussion groups were carried out with 30 adults aged 49-60 years (60% female). Information about different aspects of the tests (e.g. sensitivity, practical issues) was presented sequentially using a semi-structured, step-by-step topic guide. Discussions were recorded and analyzed using framework analysis. RESULTS: CTC was favored on the parameters of invasiveness, extra-colonic evaluation and interference with daily life, whereas sensitivity, avoiding false-positives and the capacity to remove polyps immediately were perceived to be important advantages of colonoscopy. Ultimately, there was no strong preference for either test: with 46% preferring colonoscopy vs. 42% for CTC. CONCLUSION: With comprehensive information, colonoscopy and CTC were seen as having different advantages and disadvantages, yielding no clear preferences between the two. The sensitivity of colonoscopy was a decisive factor for some people, but the lower invasiveness of CTC was seen as an asset in the screening context. PRACTICE IMPLICATIONS: CTC may be an acceptable alternative to colonoscopy in CRC screening. Healthcare professionals working in the screening context should be sensitive to the range of characteristics that can determine preferences for CRC screening tests.

Automatic prone to supine haustral fold matching in CT colonography using a Markov random field model.

CT colonography is routinely performed with the patient prone and supine to differentiate fixed colonic pathology from mobile faecal residue. We propose a novel method to automatically establish correspondence. Haustral folds are detected using a graph cut method applied to a surface curvature-based metric, where image patches are generated using endoluminal CT colonography surface rendering. The intensity difference between image pairs, along with additional neighbourhood information to enforce geometric constraints, are used with a Markov Random Field (MRF) model to estimate the fold labelling assignment. The method achieved fold matching accuracy of 83.1% and 88.5% with and without local colonic collapse. Moreover, it improves an existing surface-based registration algorithm, decreasing mean registration error from 9.7mm to 7.7mm in cases exhibiting collapse.

Evidence review and status update on computed tomography colonography.

Computed tomographic (CT) colonography is being implemented increasingly in the USA and Europe, and in many centers it has become the radiological technique of choice for imaging the whole colorectum. Although high diagnostic accuracy has been demonstrated in both screening and symptomatic populations, controversy persists regarding implementation, who should interpret the examination, and its cost effectiveness, particularly in the context of primary colorectal cancer screening. Published research in recent years has demonstrated efficacy in a wide range of patient groups, striking technical improvements, and high levels of patient acceptability. New developments continue in the fields of computer aided detection, digital cleansing, and integration into positron emission tomography. The purpose of this review is to bring the reader up-to-date with the latest developments in CT colonography, in particular, those of the last year.