A random sampling approach for robust estimation of tissue-to-plasma ratio from extremely sparse data.
his study was performed to develop a new nonparametric approach for the estimation of robust tissue-to-plasma ratio from extremely sparsely sampled paired data (ie, one sample each from plasma and tissue per subject). Tissue-to-plasma ratio was estimated from paired/unpaired experimental data using independent time points approach, area under the curve (AUC) values calculated with the naïve data averaging approach, and AUC values calculated using sampling based approaches (eg, the pseudoprofile-based bootstrap [PpbB] approach and the random sampling approach [our proposed approach]). The random sampling approach involves the use of a 2-phase algorithm. The convergence of the sampling/resampling approaches was investigated, as well as the robustness of the estimates produced by different approaches. To evaluate the latter, new data sets were generated by introducing outlier(s) into the real data set. One to 2 concentration values were inflated by 10% to 40% from their original values to produce the outliers. Tissue-to-plasma ratios computed using the independent time points approach varied between 0 and 50 across time points. The ratio obtained from AUC values acquired using the naive data averaging approach was not associated with any measure of uncertainty or variability. Calculating the ratio without regard to pairing yielded poorer estimates. The random sampling and pseudoprofile-based bootstrap approaches yielded tissue-to-plasma ratios with uncertainty and variability. However, the random sampling approach, because of the 2-phase nature of its algorithm, yielded more robust estimates and required fewer replications. Therefore, a 2-phase random sampling approach is proposed for the robust estimation of tissue-to-plasma ratio from extremely sparsely sampled data.
Chu
Hui-May
HM
Department of Clinical Pharmacology, Vertex Pharmaceuticals Inc, 130 Waverly Street, Cambridge, MA 02139-4242, USA. Hui-May_Chu@vrtx.com
Ette
Ene I
EI
D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D010599:Pharmacokinetics; D010949:Plasma / Q000737:chemistry*; D011897:Random Allocation; D051381:Rats; D012494:Sampling Studies; D018709:Statistics, Nonparametric; D014116:Toxicology / Q000706:statistics & numerical data*