Importance of incorporating quantitative imaging biomarker technical performance characteristics when estimating treatment effects.

ABSTRACT

BACKGROUND/AIMS: Quantitative imaging biomarkers have the potential to detect change in disease early and noninvasively, providing information about the diagnosis and prognosis of a patient, aiding in monitoring disease, and informing when therapy is effective. In clinical trials testing new therapies, there has been a tendency to ignore the variability and bias in quantitative imaging biomarker measurements. Unfortunately, this can lead to underpowered studies and incorrect estimates of the treatment effect. We illustrate the problem when non-constant measurement bias is ignored and show how treatment effect estimates can be corrected. METHODS: Monte Carlo simulation was used to assess the coverage of 95% confidence intervals for the treatment effect when non-constant bias is ignored versus when the bias is corrected for. Three examples are presented to illustrate the methods: doubling times of lung nodules, rates of change in brain atrophy in progressive multiple sclerosis clinical trials, and changes in proton-density fat fraction in trials for patients with nonalcoholic fatty liver disease. RESULTS: Incorrectly assuming that the measurement bias is constant leads to 95% confidence intervals for the treatment effect with reduced coverage (<95%); the coverage is especially reduced when the quantitative imaging biomarker measurements have good precision and/or there is a large treatment effect. Estimates of the measurement bias from technical performance validation studies can be used to correct the confidence intervals for the treatment effect. CONCLUSION: Technical performance validation studies of quantitative imaging biomarkers are needed to supplement clinical trial data to provide unbiased estimates of the treatment effect.