The question addressed by this health technology assessment (HTA) is as set out in the final scope published by the National Institute for Health Research (NIHR), and is reproduced here for reader convenience.
A protocol was developed a priori by the authors to address the decision problem.
The methods used to address specific aspects of the decision problem are detailed at the beginning of each of the relevant chapters which follow.
Test accuracy review question
What is the accuracy of tumour-based tests for LS in all newly diagnosed persons with CRC under 50 years of age, and those considered according to clinical criteria to be at high risk?
Population
All newly diagnosed patients under the age of 50 years with CRC.
Participants considered to be at high risk of LS, i.e. those fulfilling AC II or Bethesda criteria.
Individuals with personal cancer history or FH indicators.
Intervention
Tumour-based tests for evidence of mutations in the genes encoding the MLH1, MSH2, MSH6 and PMS2 DNA MMR enzymes. These tests include MSI, IHC, BRAF and methylation.
Comparators
Genetic testing by sequencing followed by MLPA is considered the gold standard.
Design
An evidence synthesis by systematic review to determine the accuracy of tumour-based tests.
Health-care setting
Primary and secondary care settings.
Test outcomes
The outcomes of interest include measures of:
diagnostic test accuracy
test failure rate
discordant test results.
Decision problem
We will compare genetic testing of all identifiable close relatives with no genetic testing (extreme case analysis) and with a level of genetic testing similar to that carried out in the local health-care setting, which we believe is reasonably typical of current practice across the NHS.
For clarity we would restate and define the suggested specific outcomes contributing to the general aim of assessing effectiveness, cost-effectiveness and cost–utility, as follows:
diagnostic accuracy of identifying LS in those presenting with CRC < 50 years of age
patient outcome, considering both quantity and quality of life, in those presenting with CRC < 50 years of age
diagnostic accuracy of identifying LS in close family members of those presenting with CRC < 50 years of age
patient outcome, considering both quantity and quality of life, in close family members of those presenting with CRC < 50 years of age
contributing to patient outcome, the number of cancers, particularly CRCs detected, their severity and their age at onset
cost of alternative strategies
contributing to cost (and patient outcome), the number of surveillance investigations, particularly check colonoscopies, undertaken.
Outcomes of interest are the cost-effectiveness and cost–utility of different strategies for testing probands and their close relatives, the diagnostic accuracy and yield of different strategies for high-risk subjects, and cases of surveillance avoided. Data on these outcomes are likely to be used along with clinical utility scores to estimate quality-adjusted life-years (QALYs).
Modelling will be employed to identify the cost-effectiveness of strategies for the investigation of all new cases of CRC in individuals < 50 years of age for markers of HNPCC. The models will explore the yield of individuals at high risk of HNPCC among the close relatives of probands and identify to what extent unnecessary surveillance (by colonoscopy or other methods) can be avoided. The analysis will also briefly examine whether or not it could be more cost-effective to undertake genetic testing alone without IHC or MSI.
Cost considerations
The cost analysis will be based on the UK NHS setting and will be from an NHS and Personal Social Services (PSS) perspective.
The costs for consideration include:
cost of equipment, any additional tests (pre screening), reagents and consumables, participation in NEQAS
staff and training of staff
maintenance of equipment
costs associated with surgeon time and the management of operating theatre time
medical costs arising from ongoing care following test results, including those associated with clinical genetics, surgery, time spent in hospital and treatment of cancer.
