Evaluation of bias,precision, robustness and runtime for estimation methods in NONMEM 7

NONMEM is the most widely used software for population pharmacokinetic (PK)-pharmacodynamic (PD) analyses. The latest version, NONMEM 7 (NM7), includes several sampling-based estimation methods in addition to the classical methods. In this study, performance of the estimation methods available in NM7 was investigated with respect to bias, precision, robustness and runtime for a diverse set of PD models. Simulations of 500 data sets from each PD model were reanalyzed with the available estimation methods to investigate bias and precision. Simulations of 100 data sets were used to investigate robustness by comparing final estimates obtained after estimations starting from the true parameter values and initial estimates randomly generated using the CHAIN feature in NM7. Average estimation time for each algorithm and each model was calculated from the runtimes reported by NM7. The method giving the lowest bias and highest precision across models was importance sampling, closely followed by FOCE/LAPLACE and stochastic approximation expectation-maximization. The methods relative robustness differed between models and no method showed clear superior performance. FOCE/LAPLACE was the method with the shortest runtime for all models, followed by iterative two-stage. The Bayesian Markov Chain Monte Carlo method, used in this study for point estimation, performed worst in all tested metrics.     

Approaches for modeling within subject variability in pharmacometric count data analysis: dynamic inter-occasion variability and stochastic differential equations

Parameter variation in pharmacometric analysis studies can be characterized as within subject parameter variability (WSV) in pharmacometric models. WSV has previously been successfully modeled using inter-occasion variability (IOV), but also stochastic differential equations (SDEs). In this study, two approaches, dynamic inter-occasion variability (dIOV) and adapted stochastic differential equations, were proposed to investigate WSV in pharmacometric count data analysis. These approaches were applied to published count models for seizure counts and Likert pain scores. Both approaches improved the model fits significantly. In addition, stochastic simulation and estimation were used to explore further the capability of the two approaches to diagnose and improve models where existing WSV is not recognized. The results of simulations confirmed the gain in introducing WSV as dIOV and SDEs when parameters vary randomly over time. Further, the approaches were also informative as diagnostics of model misspecification, when parameters changed systematically over time but this was not recognized in the structural model. The proposed approaches in this study offer strategies to characterize WSV and are not restricted to count data.     

The Study on Produce and Properties ofF-Heparin Surface Modified IOLs

INTRODUCTION　　 At present,the hard intraocular lens( IOL) used clinically is made of poly-methylmethacrylate( PMMA) .However,PMMA is notbiologically inert,many ar-ticles have reported that PMMA IOLs can lead to some reactions,such as inflamma-tory response,immune reaction,deposition of cells and pigments on the surface of IOLs and opacification of the posterior capsule( PCO) .How to increase the biocom-patibility of IOLs has been the hotspot of many scholars.　　In our centre…     

Efficacy and cost of home-initiated auto-nCPAP versus conventional nCPAP

STUDY OBJECTIVES: To compare in a multicenter prospective study the efficacy and cost of conventional nasal continuous positive airway pressure (nCPAP) initiated at the sleep laboratory versus auto-nCPAP initiated at home. DESIGN: Patients with severe obstructive sleep apnea syndrome (OSAS) were randomized to treatment with either the REM+ auto device in constant mode at the effective pressure determined by titration at the sleep laboratory (n=17) or the REM+ auto device in automatic mode initiated at the patients home by a nurse (n=18). After 2 months, the efficacy and cost of nCPAP therapy and the time from diagnosis to nCPAP were evaluated. All values are reported as means +/- SD. PATIENTS: Thirty-five subjects with newly diagnosed OSAS (8 women and 27 men, mean age: 54.3 +/- 10.6 years, apnea-hypopnea index (AHI) 58.1 +/- 14.0 h(-1)). INTERVENTIONS: N/A MEASUREMENTS AND RESULTS: Both treatments were used properly and induced similar decreases in the AHI (7.6 +/- 6.9 vs. 10.4 +/ -12.5 h(-1) for auto-nCPAP and conventional nCPAP, respectively; NS) and Epworth Sleepiness score (from 15.5 +/- 4.7 to 7.5 +/- 3.4 vs. 14.7 +/- 3.9 to 7.6 +/- 3.4 for auto-nCPAP and conventional nCPAP, respectively; NS). With auto-nCPAP initiated at home, the time from diagnosis to final adjustment of nCPAP was shorter (16.3 +/- 5.0 vs. 47.2 +/- 46.5 days with conventional nCPAP, P < 0.02) and the cost was lower (1,263 +/- 352 vs. 1720+/-455 E, respectively; P < 0.05). CONCLUSIONS: Treatment of OSAS with auto-nCPAP initiated at home is effective and reliable and reduces the time from diagnosis to therapy and the cost of treatment.