RE: Negative concentration from simulation

Hi Nyein, For drug concentrations the additive error model assumes that the background noise is random with mean zero when the drug concentration is truly zero. In the real world there is always background noise for measurements which means that real measurements can appear to be a negative concentration even though the true concentration is zero. Simulations that simulate negative concentrations are therefore more realistic than those that ignore reality and are reported as censored measurement values. The honest thing to do is to report measurements as they are. The dishonest thing is to report real measurements as below some arbitrary limit of quantification. There are numerous papers which describe the bias arising from dishonest reporting of real measurements and work arounds if you have to deal with this kind of scientific fraud e.g. Beal SL. Ways to fit a PK model with some data below the quantification limit. Journal of Pharmacokinetics & Pharmacodynamics. 2001;28(5):481-504. Duval V, Karlsson MO. Impact of omission or replacement of data below the limit of quantification on parameter estimates in a two-compartment model. Pharm Res. 2002;19(12):1835-40. Ahn JE, Karlsson MO, Dunne A, Ludden TM. Likelihood based approaches to handling data below the quantification limit using NONMEM VI. J Pharmacokinet Pharmacodyn. 2008;35(4):401-21. Byon W, Fletcher CV, Brundage RC. Impact of censoring data below an arbitrary quantification limit on structural model misspecification. J Pharmacokinet Pharmacodyn. 2008;35(1):101-16. Senn S, Holford N, Hockey H. The ghosts of departed quantities: approaches to dealing with observations below the limit of quantitation. Stat Med. 2012;31(30):4280-95. Keizer RJ, Jansen RS, Rosing H, Thijssen B, Beijnen JH, Schellens JHM, et al. Incorporation of concentration data below the limit of quantification in population pharmacokinetic analyses. Pharmacology research & perspectives. 2015;3(2):10.1002/prp2.131 Best wishes, Nick -- Nick Holford, Professor Clinical Pharmacology Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand office:+64(9)923-6730 mobile:NZ+64(21)46 23 53 FR+33(6)62 32 46 72 email: [email protected] http://holford.fmhs.auckland.ac.nz/ http://orcid.org/0000-0002-4031-2514 Read the question, answer the question, attempt all questions