Stratified medicine: methods for evaluation of predictive biomarkers

Background: Stratified medicine was defined as the use of biomarkers to select patients more likely to respond to a treatment or experience an adverse event. Alms: To investigate the hypothesis that there is a mismatch between the theoretical proposals and practice of predictive biomarker research, focusing on the clinical utility stage. Methods: Methodological research was identified in a systematic review of frameworks for staged evaluation of predictive biomarkers. Actual research supporting 50 real cases identified in European Medicines Agency licensing was analysed. A case study of recent research into ERCC l in non-small cell lung cancer was undertaken. Existing discrepancies between the theory and practice were identified and possible reasons and consequences of these were discussed. Findings: A mismatch between theory and practice was identified. It appeared to be a result of both the practice not following some theoretical requirements, and the underdevelopment of methodology for certain situations. Areas of clinical research with insufficient relevant methodology were identified. Conclusions: The major research priorities identified in this thesis were development of a clear hierarchy of biomarker research designs and development of methodology related to the biomarker threshold

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]