Developing a framework for assessing the impact of test measurement uncertainty on clinical and health-economic outcomes

Background: Many factors can introduce uncertainty into medical laboratory test measurements, and this uncertainty can affect downstream clinical and health-economic outcomes. Currently, however, the impact of measurement uncertainty on outcomes is rarely considered, either within laboratory medicine or Health Technology Assessment (HTA) practices.

Aim: To develop a framework for assessing the impact of test measurement uncertainty on clinical and health-economic outcomes.

Methods: Five hypotheses were addressed in this thesis. Hypothesis A – that measurement uncertainty has not been routinely addressed within HTAs – was assessed via a systematic review of HTAs. Hypothesis B – that methods for assessing the impact of measurement uncertainty on outcomes have been used in the broader literature – was assessed via a methodology literature review. The remaining hypotheses – that methods from the literature could be used/adapted to: [C] evaluate the impact of measurement uncertainty on clinical performance, utility and cost-effectiveness; [D] derive outcome-based analytical performance specifications (APS); and [E] accommodate real world evidence on measurement performance – were assessed via a case study analysis, exploring the role of faecal calprotectin for the diagnosis of Inflammatory Bowel Disease (IBD).

Results: The HTA review confirmed that, to date, HTAs have rarely assessed the impact of measurement uncertainty on outcomes. The methodology review, meanwhile, identified various relevant methods from the broader literature (mostly from the laboratory medicine field). Of those, iterative simulation and decision modelling were selected for further exploration based on their ability to be integrated into existing HTA methodology. The subsequent case study demonstrated a framework of analysis building on these methods. Using both hypothetical and real world evidence simulations, the robustness of faecal calprotectin clinical pathway outcomes to increasing measurement uncertainty was assessed, and regions of acceptable measurement uncertainty (i.e. outcome-based APS) were identified.

Conclusions: The presented framework can help to improve HTA-decision making and inform outcome-based laboratory practices.