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In several investigations of molecular imaging of angiogenic neovasculature using a targeted contrast agent, Renyi entropy (If(r)) and a limiting form of Renyi entropy (If,∞) exhibited significantly more sensitivity to subtle changes in scattering architecture than energy-based methods. Many of these studies required the fitting of a cubic spline to backscattered waveforms prior to calculation of entropy (either If(r) or If,∞)In this study it is shown that the robustness of If,∞ may be improved by using a smoothing spline. Results are presented showing the impact of different smoothing parameters. In addition, if smoothing is preceded by lowpass filtering of the waveforms, further improvements may be obtained.