On the identifiability of pharmacokinetic parameters in dynamic contrast-enhanced imaging

The so-called "Kety model" is a two-compartment pharmacokinetic model describing tumor perfusion kinetics. Its parameters, the transendothelial transfer constant (K(trans)), extravascular extracellular volume fraction (v(e)), and microvascular plasma volume fraction (v(p)), can be estimated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). However, the results obtained by current methods show large variation in predictability and reliability. Here, the aim was to examine which experimental conditions have to be fulfilled to avoid large uncertainties and mutual dependencies of the parameters. Using frequency response analysis and simulation, the identifiability of the model was examined. The requirements and influence of contrast enhancement measurements, such as temporal resolution, signal to noise ratio, and contrast injection rate, on the accuracy of the parameters were analyzed. Tissue response characteristics revealed a low-frequency system with a cutoff frequency equal to K(trans)/v(e), which confines the required temporal resolution. For malignant tissue with hyperpermeable vasculature (high K(trans)) a higher sampling frequency is required to accurately estimate K(trans) than for normal tissue. Too low sampling rates or too low injection rates resulted in inaccurate K(trans) values and hereby unreliable classification of malignant tissue.