Note from the National Guideline Clearinghouse (NGC): The National Institute for Health and Care Excellence (NICE) commissioned an External Assessment Group to perform a systematic literature review on the technology considered in this diagnostics guidance and prepare a Diagnostics Assessment Report (DAR). The DAR for this guidance was prepared by Kleijnen Systematic Reviews Ltd. in collaboration with Erasmus University Rotterdam and Maastricht University (see the "Availability of Companion Documents" field).
Assessment of Clinical Effectiveness
Data relating to study details, participants, intervention and comparator tests, reference standard, and outcome measures were extracted by one reviewer, using a piloted, standard data extraction form. A second reviewer checked data extraction and any disagreements were resolved by consensus.
The evidence-based Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool, is recommended for assessing the methodological quality of test accuracy studies. A revised version of QUADAS (QUADAS-2) has recently been published (www.QUADAS.org ). QUADAS-2 more closely resembles the approach and structure of the Cochrane risk of bias tool. It is divided into four key domains covering participant selection, index test, reference standard, and the flow of patients through the study (including timing of tests). Each domain is rated for risk of bias (low, high, or unclear) and the tool provides signalling questions, in each domain, to aid reviewers in reaching a judgement. The participant selection, index test and reference standard domains are also separately rated for concerns regarding the applicability of the study to the review question (low, high, or unclear). Thus, QUADAS-2 separates bias from external validity (applicability) and does not include any items which only assess reporting quality. The QUADAS-2 tool does not currently include domains specific to the assessment of studies comparing multiple index tests, such as those included in this assessment. Further development of QUADAS-2 in this area is planned. A modified version of the QUADAS-2 tool, which includes an additional domain for the comparator test and additional signalling questions in the 'flow and timing' domain, has been used in this assessment. Review-specific guidance was produced for the use of the modified version of QUADAS-2 and is reported in Appendix 2 in the DAR.
The results of the quality assessment are summarised and presented in tables and graphs in the results of the systematic review (Section 4.6) and are presented in full, by study, in Appendix 3 in the DAR. No diagnostic accuracy data set included in this assessment was of sufficient size to allow statistical exploration of between study heterogeneity based on aspects of risk of bias. The findings of the quality assessment were used to inform recommendations for future research. The risk of bias in the controlled clinical trial was assessed using a table based on the Cochrane Collaboration's tool for assessing risk of bias.
The methodological quality of included effectiveness studies was assessed using standard tools. The Cochrane Collaboration quality assessment checklist was used to assess the methodological quality of each included study as detailed in Table 2 in the DAR.
Each study was awarded a 'yes', 'no' or 'unclear/unknown' rating for each individual item in the checklist. Any additional clarifications or comments were also recorded.
The quality of case-control and cohort studies was assessed using specific checklists for the methodological quality assessment of these studies. In addition, the Assessment Group used an adapted version of the quality assessment checklist by Wedlake et al. (ee Appendix 2 in the DAR).
Quality assessment was carried out independently by two reviewers. Any disagreements were resolved by consensus.
Methods of Analysis/Synthesis
Meta-analysis was considered inappropriate, due to the small number of test accuracy studies with varying diagnostic thresholds and between study heterogeneity in other study design categories (principal diagnosis, treatment dose, definition of response, follow-up period and tauroselcholic [75selenium] acid [SeHCAT] administration); the Assessment Group, therefore employed a narrative synthesis. Typically, this involved the use of text and tables to summarise data. Studies were organised by clinical application (diagnosis of bile acid malabsorption [BAM] in those with chronic diarrhoea and those with Crohn's disease) and study design (diagnostic test accuracy studies [DTAs], observational studies of treatment effect in SeHCAT positive patients, and randomised controlled trial [RCT] of bile acid sequestrants [BAS] treatment in patients without SeHCAT testing). Text summaries were supported by tables and figures as appropriate.
As no studies were found for the assessment of SeHCAT's test accuracy and very few studies for the accuracy of SeHCAT to predict treatment response, it was decided to include studies reporting response to BAS given a positive test to estimate the probability of a positive BAS response at different SeHCAT cut off points. Based on the data retrieved, a random effects meta-analysis was performed to find a pooled estimate for each of the three cut-off values.
Statistical analyses were performed using the following software: RevMan (version 5), Comprehensive Meta-Analyses (CMA version 2), and STATA (STATA™ for Windows, version 10, Stata Corp; College Station, TX).
See Section 4 in the DAR for additional information on assessment of clinical effectiveness.
Model Structure and Methodology
As no relevant models were identified in the searches, a de novo model was developed for each population. This model consists of two parts, a decision model reflecting the diagnostic and initial treatment phase and a Markov model to estimate long term costs and effects. The Assessment Group compares various strategies.
The scoping document clearly defined SeHCAT and no SeHCAT as strategies. The option of Trial of treatment was also mentioned without specifically including it as a comparator. According to the clinical experts at the scoping meeting, Trial of treatment is rarely used as a treatment strategy and was thus not considered relevant. However, Trial of treatment can also not be completely excluded as an option. Thus, in this report the Assessment Group presents two sets of results: one where Trial of treatment is not considered as a comparator and one where it is.
For the diarrhoea-predominant inflammatory bowel disease (IBS-D) population the Assessment Groups compares first the SeHCAT strategy using 3 different cut-off points (absorption <5%, <10% and <15%) with no SeHCAT testing, i.e., treating patients as IBS-D patients. In the second set of results, Trial of treatment is added as a strategy. For the Crohn's population, the same strategies are included with the exception of SeHCAT 5%, as no data was available for this strategy. In this population, No SeHCAT entails treatment for the chronic diarrhoea (which may or may not be a direct result of a disease relapse).
The models used in the analyses are described in detail. The stochastic analyses are based on cohort simulations. To investigate decision uncertainty, second-order uncertainty micro-simulations were run. All costs and effects were discounted by 3.5%. The model incorporated a lifetime horizon to estimate outcomes in terms of quality-adjusted life years (QALYs) and costs from the perspective of the National Health Service (NHS). Only health effects of patients were included.
See Section 5 in the DAR for more information on cost-effectiveness assessment.