Dr Andrew Leary ★ Ireland, 20071120 15:50 (5796 d 02:07 ago) Posting: # 1312 Views: 17,423 

Dear Helmut I hope that Berlin went well. I contacted you directly earlier this year with a question about the replicate design. You will be glad to see that this time I've used the Forum as requested! My statistician has the following question: My question is how to calculate intrasubject CV's for a 4period 2treatment replicate bioequivalence trial which I intend to analyze using proc mixed (SAS). I have analysed crossover bioequivalence trials before and used the formula 100%(e^MSE1)^0.5 to calculate itrasubject CV where MSE is the mean square error. MSE was claculated using proc glm. How should I calculate MSE this time? Do I calculate two separate ANOVA models for each treatment and use the different MSE's from each analysis to give separate intrasubject CV's or do I take a completly different approach? I hope that you can help. Kind regards Dr Andrew Leary [Shandon Clinic, Cork, IRELAND] 
Helmut ★★★ Vienna, Austria, 20071120 17:27 (5796 d 00:30 ago) @ Dr Andrew Leary Posting: # 1313 Views: 15,135 

Dear Andrew! ❝ I hope that Berlin went well. Actually right now I'm sitting in the conference hall and will be chairing the meeting tomorrow; so please be a little patient  maybe another member of the forum can fill in the gap in the meantime... — Diftor heh smusma 🖖🏼 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Dr Andrew Leary ★ Ireland, 20071120 17:46 (5796 d 00:10 ago) @ Helmut Posting: # 1314 Views: 15,116 

We'll be patient. Data is not due back for another 23 weeks!  Edit: Full quote removed. [HS] 
Dr Andrew Leary ★ Ireland, 20071205 17:35 (5781 d 00:22 ago) @ Dr Andrew Leary Posting: # 1356 Views: 15,058 

Hello Helmut Any word on the query (in red) below? Kind regards Andrew Leary ❝ My question is how to calculate intrasubject CV's for a 4period 2treatment replicate bioequivalence trial which I intend to analyze using proc mixed (SAS). I have analysed crossover bioequivalence trials before and used the formula 100%(e^MSE1)^0.5 to calculate itrasubject CV where MSE is the mean square error. MSE was claculated using proc glm. How should I calculate MSE this time? Do I calculate two separate ANOVA models for each treatment and use the different MSE's from each analysis to give separate intrasubject CV's or do I take a completly different approach? 
ddubins ☆ Toronto, 20080301 20:28 (5693 d 21:28 ago) @ Dr Andrew Leary Posting: # 1652 Views: 16,028 

Hi Andrew, It's a bit late for this reply, but I found the answer to your question. You don't need to run proc GLM. The replicate SAS output gives all of the information you need to calculate intra and interCV, where it outputs the covariate matrix ("Covariate Parameter Estimates"). The SAS output might look like this: Covariate Parameter Estimates Cov Parm Subject Group Estimate FA(1,1) Subject 0.5928 < (sig_BT, the betweensubject standard deviation for the Test product) FA(2,1) Subject 0.4968 < (sig_BR, the betweensubject standard deviation for the Reference product) FA(2,2) Subject 2E17 < (sig_D, the subjectbyformulation interaction term) Residual Subject Treatment A 0.124 < (sig_WT^2, the withinsubject standard deviation for the Test product) Residual Subject Treatment B 0.242 < (sig_WR^2, the withinsubject standard deviation for the Reference product) The intrasubject variabilities are still calculated from the residuals as in a 2way crossover, using: IntraCV_T = 100%*sqrt(exp(sig_WT^2)1) (in this case, = 100*sqrt(exp(0.124)1) = 36.3% IntraCV_R = 100%*sqrt(exp(sig_WR^2)1) (in this case, = 100*sqrt(exp(0.242)1) = 52.3% FA(1,1) and FA(2,1) are the intersubject standard deviations for Test and Reference products, respectively: InterCV_T = 100%*sqrt(exp(sig_BT^2)1) = 100*sqrt(exp(0.5928^2)1) = 64.9% IntraCV_R = 100%*sqrt(exp(sig_BR^2)1) = 100*sqrt(exp(0.4968^2)1) = 52.9% Hope this helps, Dave — David Dubins, Ph.D., B.A.Sc. Associate Professor, Teaching Stream Director, Pharmaceutical Chemistry Specialist Program Leslie Dan Faculty of Pharmacy University of Toronto 144 College Street (room PB802), Toronto, ON M5S 3M2 Tel. +1 4169465303; FAX: +1 416 9788511 
Helmut ★★★ Vienna, Austria, 20080302 14:01 (5693 d 03:56 ago) @ ddubins Posting: # 1653 Views: 14,899 

— Diftor heh smusma 🖖🏼 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
d_labes ★★★ Berlin, Germany, 20080303 13:05 (5692 d 04:52 ago) @ ddubins Posting: # 1654 Views: 15,533 

Hello David, i agree with your assignment of the intraindividual error terms. ❝ Covariate Parameter Estimates ❝ Cov Parm Subject Group Estimate ❝ FA(1,1) Subject 0.5928 < (sig_BT, the betweensubject standard ❝ deviation for the Test product) ❝ FA(2,1) Subject 0.4968 < (sig_BR, the betweensubject standard ❝ deviation for the Reference product) ❝ FA(2,2) Subject 2E17 < (sig_D, the subjectbyformulation ❝ interaction term) But your assignment of the FA(i,i) terms to the interindividual (co)variances is not correct i think. Think of the G matrix (using your notation):
G(1,1) = sig_BT^{2} Futher it is defined (subjectbyformulation interaction variance)
sig_D^{2}=G(1,1)+G(2,2)2*G(1,2) The FA0(2) parameterization of the GMatrix reads
G(1,1)=FA(1,1)^{2} Confer to the SAS documentation for this. By the way: G(1,1) = sig_BT^{2} is only valid, if your coding of test treatment preceedes that of the reference. Thus with some algebra you obtain
FA(1,1)=sig_BT Thus your assignment of FA(2,1) is only valid if rho=1 which implies FA(2,2)=0. In that case the subjectbyformulation interaction variance is
sig_D^{2}=FA(1,1)^{2}+FA(2,1)^{2}2*FA(1,1)*FA(2,1) — Regards, Detlew 
Sathya ☆ India, 20080920 10:17 (5491 d 08:40 ago) @ d_labes Posting: # 2380 Views: 14,564 

Hello d_labes, This is Sathya Again. Now I am trying to precede 4 period, 2 treatment, and 4 sequence studies (by using the dataset from the link given by you) SAS Code – Proc Mixed : forum_entry.php?id=1589 Intra_CV Calculation : forum_entry.php?id=1652 Inter_Cv Calculation : forum_entry.php?id=1654 The above links are my major reference for this study. Further it is defined (subjectbyformulation interaction variance) sig_D2=G (1, 1) +G (2, 2)2*G (1, 2) How can I find rho by using SAS? And how can I get G matrix in SAS? I tried with G and Gcorr. But I am unable to get G (1, 1), G (2, 2) and G (1, 2). I got the following result for G and G CORR Estimated G Correlation Matrix Labes, I already said that, I am a beginner. So please help me in documentation too. What are things I have to submit to the client company generally if BA/BE studies was given to us? What are the calculations or parameter must be in SAS report for BA/BE? If once replicate design will give to us for BA/BE study Whether We has to do PBE/ IBE or it depends upon the client requirement? What else the document I have to submit? Please give me clarity. — Sathya 
d_labes ★★★ Berlin, Germany, 20080922 13:35 (5489 d 05:22 ago) @ Sathya Posting: # 2381 Views: 14,664 

Dear Sathya, ❝ How can I find rho by using SAS? ❝ And how can I get G matrix in SAS? I tried with G and Gcorr. But I am ❝ unable to get G (1, 1), G (2, 2) and G (1, 2). Look at your SAS output of Proc MIXED again. If you use the G option you will have a piece of output named "Estimated G Matrix". G(i,j) is the element with row i and column j. For instance:
Row Effect treat. Subject Col1 Col2 Here G(1,1) is 0.1181, G(1,2) is 0.1058 and so on. Yes, its that easy with matrices. Try to remember your math courses on that! They are not the same thing as Matratzen (German word, in english mattresses). Why do you need rho? If you are interested in, take the formulas above in this thread, a little puzzled math and you have a formula for rho from the elements of the G matrix. I left this for your excercise. The option GCORR gives you a value of rho in the offdiagonal element of the "Estimated G Correlation Matrix". Or parameterize with the CSH structure instead of FA0(2) (look at your SAS/Stat manual) and you will get directly an estimate of rho under "Covariance Parameter Estimates". Its name is CSH in the SAS output. For the rest of your questions: They look like the question "How can I earn a lot of money?". How shall I answer this? Have a look at the Guidance of the country you will submit to. There are in most cases enough hints what you have to submit (up to such very special and detailed wishes of the regulators in the new EMEA draft 'The presentation of the findings of a bioequivalence trial should include a 2x2table that presents for each sequence (in rows) and each period (in columns) means, standard deviations and number of observations for the observations in the respective period of a sequence.'). Concerning PBE/IBE search the forum and look again into Guidances. You will find that usually no regulatory body will request this. — Regards, Detlew 
Helmut ★★★ Vienna, Austria, 20080922 13:47 (5489 d 05:10 ago) @ d_labes Posting: # 2382 Views: 14,427 

Matritzen # Matratzen — Diftor heh smusma 🖖🏼 Довге життя Україна! _{} Helmut Schütz The quality of responses received is directly proportional to the quality of the question asked. 🚮 Science Quotes 
Sathya ☆ India, 20080924 13:02 (5487 d 05:55 ago) @ d_labes Posting: # 2392 Views: 14,466 

Dear d_labes, Thank you very much for your responses. I didnot ask you that "How can I earn a lot of money?" . i just asked "will you give me your live experience on earning money?". It will prevent me from the disasters and guide me in right way. If my questions disturb you then forgive me. But your help is much worth. Thanks a lot. Now i am concentrate on the guidelines. And i find out the value of rho in the offdiagonal element of the "Estimated G Correlation Matrix". once again Thank you. — Sathya 
d_labes ★★★ Berlin, Germany, 20080924 14:46 (5487 d 04:10 ago) @ Sathya Posting: # 2393 Views: 14,364 

Dear Sathya, my intention was not to bother you. It was the sort of question I meant, so generic, that prevent a reasonable answer. — Regards, Detlew 
Sathya ☆ India, 20080925 08:02 (5486 d 10:55 ago) @ d_labes Posting: # 2398 Views: 14,367 

Dear d_labes, Thank you. — Sathya 