Indexed distribution analysis for improved significance testing of spatially heterogeneous parameter maps: application to dynamic contrast-enhanced MRI biomarkers.

ABSTRACT

PURPOSE: To develop significance testing methodology applicable to spatially heterogeneous parametric maps of biophysical and physiological measurements arising from imaging studies. THEORY Heterogeneity can confound statistical analyses. Indexed distribution analysis (IDA) transforms a reference distribution, establishing correspondences across parameter maps to which significance tests are applied. METHODS: Well-controlled simulated and clinical K(trans) data from a dynamic contrast-enhanced magnetic resonance imaging study of bevacizumab were analyzed using conventional significance tests of parameter averages, histogram analysis, and IDA. Repeated pretreatment scans provided negative control; a post treatment scan provided positive control. RESULTS: Histogram analysis was insensitive to simulated and known effects. Simulation conventional analysis identified treatment effect (P ≈ 5 × 10(-4)) and direction, but underestimated magnitude (relative error 67-81%); IDA identified treatment effect (P = 0.001), magnitude, direction, and spatial extent (100% accuracy). Bevacizumab conventional analysis was sensitive to treatment effect (P = 0.01; 95% confidence interval on K(trans) decrease 23-37%); IDA was sensitive to treatment effect (P < 0.05; K(trans) decrease approximately 25%), inferred its spatial extent to be 94-96%, and inferred that K(trans) decrease is independent of baseline value, an inference that conventional and histogram analyses cannot make. CONCLUSIONS: In the presence of heterogeneity, IDA can accurately infer the magnitude, direction, and spatial extent of between samples of parametric maps, which can be visualized spatially with respect to the original parameter maps.