Re: RE: Link different thetas to same omega using mu referencing

From: Rupert Austin <[email protected]> To: "'Sadler, Brian'" <[email protected]>; [email protected] Sent: Wednesday, April 13, 2016 11:44 AM Subject: RE: [NMusers] RE: Link different thetas to same omega using mu referencing #yiv7090570546 #yiv7090570546 -- _filtered #yiv7090570546 {panose-1:2 4 5 3 5 4 6 3 2 4;} _filtered #yiv7090570546 {font-family:Calibri;panose-1:2 15 5 2 2 2 4 3 2 4;} _filtered #yiv7090570546 {font-family:Tahoma;panose-1:2 11 6 4 3 5 4 4 2 4;}#yiv7090570546 #yiv7090570546 p.yiv7090570546MsoNormal, #yiv7090570546 li.yiv7090570546MsoNormal, #yiv7090570546 div.yiv7090570546MsoNormal {margin:0cm;margin-bottom:.0001pt;font-size:11.0pt;}#yiv7090570546 a:link, #yiv7090570546 span.yiv7090570546MsoHyperlink {color:#0563C1;text-decoration:underline;}#yiv7090570546 a:visited, #yiv7090570546 span.yiv7090570546MsoHyperlinkFollowed {color:#954F72;text-decoration:underline;}#yiv7090570546 p.yiv7090570546MsoAcetate, #yiv7090570546 li.yiv7090570546MsoAcetate, #yiv7090570546 div.yiv7090570546MsoAcetate {margin:0cm;margin-bottom:.0001pt;font-size:8.0pt;}#yiv7090570546 span.yiv7090570546BalloonTextChar {}#yiv7090570546 span.yiv7090570546EmailStyle19 {color:windowtext;}#yiv7090570546 span.yiv7090570546EmailStyle20 {color:#1F497D;}#yiv7090570546 span.yiv7090570546EmailStyle21 {color:#1F497D;}#yiv7090570546 span.yiv7090570546EmailStyle23 {color:#1F497D;}#yiv7090570546 .yiv7090570546MsoChpDefault {font-size:10.0pt;} _filtered #yiv7090570546 {margin:70.85pt 70.85pt 70.85pt 70.85pt;}#yiv7090570546 div.yiv7090570546WordSection1 {}#yiv7090570546 I’m not sure that Brian’s suggestion is acceptable due to the following constraint I quote from one of the NONMEM manuals: “Time dependent covariates cannot be part of the MU_ equation” If CAT is time-varying (as suggested by Jacob) then “MU_1 = CAT1*THETA(1) + CAT2*THETA(2) + CAT3*THETA(3)” includes time dependent covariates. Rather worryingly, I don’t think NONMEM will trap this problem since I have fallen foul of it with no resulting NONMEM warnings, and I have no idea what the consequences are for the resulting NONMEM run and results. Rupert Rupert Austin, PhDSenior ScientistBAST Inc LimitedLoughborough University Science and Enterprise ParkCharnwood WingHolywell ParkAshby RoadLoughborough, LE11 3AQ, UKTel: +44 (0)1509 222908 From: [email protected] [mailto:[email protected]] On Behalf Of Sadler, Brian Sent: 13 April 2016 13:26 To: [email protected] Subject: [NMusers] RE: Link different thetas to same omega using mu referencing Hi Jacob, I suggest:CAT1=0CAT2=0CAT3=0IF(CAT.EQ.1) CAT1=1IF(CAT.EQ.2) CAT2=1IF(CAT.EQ.3) CAT3=1MU_1 = CAT1*THETA(1) + CAT2*THETA(2) + CAT3*THETA(3)CL = EXP(MU_1+ETA(1)) That way you have only one OMEGA. This could be more flexible when expanding OMEGA for additional IIV in block format. Cheers… Brian From: [email protected] [mailto:[email protected]] On Behalf Of Michael Fossler Sent: Wednesday, April 13, 2016 7:56 AM To: Leander, Jacob; [email protected] Subject: [NMusers] RE: Link different thetas to same omega using mu referencing This looks like it would work – it seems to obey the rules around mu-referencing. You can simplify the $OMEGA by using SAME(3) MikeMichael J. Fossler, Pharm. D., Ph. D., F.C.P.VP, Quantitative SciencesTrevena, [email protected]: 610-354-8840, ext. 249Cell: 610-329-6636 From: [email protected] [mailto:[email protected]] On Behalf Of Leander, Jacob Sent: Wednesday, April 13, 2016 7:01 AM To: [email protected] Subject: [NMusers] Link different thetas to same omega using mu referencing Hi Consider the case where we have a categorical (potentially time-varying) covariate named CAT that can take several values (e.g. 0,1,2,3).Let’s say I want to model CL depending on this categorical covariate (where parameters are estimated on log-scale). A simple solution to this would be IF(CAT.EQ.1) TVCL = THETA(1)IF(CAT.EQ.2) TVCL = THETA(2)IF(CAT.EQ.3) TVCL = THETA(3) I let CL be described by a log-normal distribution with the same omega element for all CAT values. CL = EXP(TVCL + ETA(1)) With an omega statement: $OMEGA 0.1 I now want to switch to the mu referencing framework in NONMEM. Each theta needs to be reference to a MU value, and to force it to be described by the same eta I apply the following approach. MU_1 = THETA(1)MU_2 = THETA(2)MU_3 = THETA(3) IF(CAT.EQ.1) CL = EXP(MU_1 + ETA(1))IF(CAT.EQ.2) CL = EXP(MU_2 + ETA(2))IF(CAT.EQ.3) CL = EXP(MU_3 + ETA(3)) With an omega statement: $OMEGA BLOCK(1) 0.1$OMEGA BLOCK(1) SAME$OMEGA BLOCK(1) SAME where I force the omega element corresponding to ETA1, ETA2 and ETA3 to be the same. Is this a valid approach to obtain what I need? Or is there a simpler way in the mu-referencing framework to link different thetas to the same omega element? All the best,Jacob Confidentiality Notice: This message is private and may contain confidential and proprietary information. If you have received this message in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this message is not permitted and may be unlawful. Notice: This e-mail message, together with any attachments, contains information of Trevena, Inc., 1018 West 8th Avenue, King of Prussia, PA 19406, USA. This information may be confidential, proprietary, copyrighted and/or legally privileged. It is intended solely for use by the individual or entity named on this message. If you are not the intended recipient, and have received this message in error, please notify us immediately and delete it and any attachments from your system.