From: hai le ba <*lebahai01*>

Date: Thu, 5 Nov 2020 14:24:50 +0100

Yes, I totally agree with you. I have tested on the other kind of dataset

(more than 1 point per ID). All of the parameters are perfectly estimated.

Now, I'm trying to find an answer for the case of 1 PK point per each ID.

And, I have this problem with the number of seed options in the SAEM method=

.

Many thanks for your suggestion.

Hai, LE Ba

Ph.D Student

La facultÃ© de Pharmacie - Aix Marseille universitÃ©

Hanoi university of Pharmacy

Email: lebahai01

hailb

bahai.le

On Thu, Nov 5, 2020 at 1:05 PM Jakob Ribbing <jakob.ribbing

*>
*

wrote:

*> I see.
*

*>
*

*> In that case this becomes kind of a theoretical exercise that can not be
*

*> applied on a real dataset.
*

*> Estimation of both IIV and sigma may be â€œfeasible" based on distr=
*

ibutional

*> assumptions.
*

*> But in reality, the random part of the parameter variability (IIV) does
*

*> not perfectly follow a log-normal distribution.
*

*> And the residual error will not be perfectly normal (additive).
*

*> From that perspective I think it is healthy that FOCE/FOCEI does not
*

*> converge, and it is not surprising that other estimation methods are ill
*

*> behaved.
*

*>
*

*> Maybe you should consider at least a percentage of subjects with multiple
*

*> observations?
*

*>
*

*> Best regards
*

*>
*

*> Jakob
*

*>
*

*>
*

*>
*

*> Jakob Ribbing, Ph.D.
*

*>
*

*> Senior Consultant, Pharmetheus AB
*

*>
*

*>
*

*> Cell/Mobile: +46 (0)70 514 33 77
*

*>
*

*> Jakob.Ribbing *

*>
*

*> www.pharmetheus.com
*

*>
*

*> Phone, Office: +46 (0)18 513 328
*

*>
*

*> Uppsala Science Park, Dag HammarskjÃ¶lds vÃ¤g 36B
*

*> SE-752 37 Uppsala, Sweden
*

*>
*

*>
*

*>
*

*> This communication is confidential and is only intended for the use of th=
*

e

*> individual or entity to which it is directed. It may contain
*

*> information that is privileged and exempt from disclosure under applicabl=
*

e

*> law. If you are not the intended recipient please notify us immediately.
*

*> Please do not copy it or disclose its contents to any other person.
*

*>
*

*>
*

*>
*

*>
*

*> On 5 Nov 2020, at 11:58, hai le ba <lebahai01 *

*>
*

*> Sorry, I've copied a wrong code of model.
*

*> The right is:
*

*> "$PK
*

*>
*

*> MU_1= LOG(THETA(1))
*

*>
*

*> KA=EXP(MU_1+ETA(1))
*

*>
*

*> MU_2=LOG(THETA(2))+ THETA(4)*LOG(AGE/60.13)
*

*> CL= EXP(MU_2+ETA(2))
*

*>
*

*> MU_3=LOG(THETA(3))+THETA(5)*LOG(WEI/66.49)
*

*> V=EXP(MU_3+ETA(3))
*

*>
*

*> S2=V
*

*> IF (TIME.LT.12) TAD=TIME
*

*> IF (TIME.GE.12.AND.TIME.LT.24) TAD=TIME-12
*

*> IF (TIME.GE.12.AND.TIME.LT.36) TAD=TIME-24
*

*> IF (TIME.GE.36.AND.TIME.LT.48) TAD=TIME-36
*

*>
*

*> $ERROR
*

*> EP1=EPS(1)
*

*> IPRED=F
*

*> IRES=DV-IPRED
*

*> W=F
*

*> IWRES=IRES/W
*

*> Y=IPRED+EPS(1)*W
*

*>
*

*> Many thanks for your support!
*

*> Best regards,
*

*>
*

*> Le jeu. 5 nov. 2020 Ã 11:15, hai le ba <lebahai01 *

©crit :

*>
*

*>> Dear Sir Jakob and Jeroen,
*

*>> Thanks for your reply.
*

*>> In fact, i've a one compartment model, with two levels of random effect
*

*>> (IIV, EPS) and covariate effect on CL, V.
*

*>> $PK
*

*>>
*

*>> MU_1= LOG(THETA(1))
*

*>>
*

*>> KA=EXP(MU_1+ETA(1))
*

*>>
*

*>> MU_2=LOG(THETA(2)+ THETA(4)*LOG(AGE/60.13))
*

*>> CL= EXP(MU_2+ETA(2))
*

*>>
*

*>> MU_3=LOG(THETA(3)+THETA(5)*LOG(WEI/66.49))
*

*>> V=EXP(MU_3+ETA(3))
*

*>>
*

*>> S2=V
*

*>> IF (TIME.LT.12) TAD=TIME
*

*>> IF (TIME.GE.12.AND.TIME.LT.24) TAD=TIME-12
*

*>> IF (TIME.GE.12.AND.TIME.LT.36) TAD=TIME-24
*

*>> IF (TIME.GE.36.AND.TIME.LT.48) TAD=TIME-36
*

*>>
*

*>> $ERROR
*

*>> EP1=EPS(1)
*

*>> IPRED=F
*

*>> IRES=DV-IPRED
*

*>> W=F
*

*>> IWRES=IRES/W
*

*>> Y=IPRED+EPS(1)*W
*

*>>
*

*>> I've used this model to simulate the complete database (10 000 IDs). Fro=
*

m

*>> this database, the smaller dataset was randomly generated with respect t=
*

o

*>> the rule of one PK sample per each ID. After that, I want to check how
*

*>> many IDs are necessary to get a good estimation for each method ( FOCEI,
*

*>> SAEM, BAYES, composite (ITS/SAEM/IMP/BAYES))?
*

*>>
*

*>> For FOCEI, I can't get convergence.
*

*>>
*

*>> For SAEM, I've got some troubles with the stability for EPS when I tried
*

*>> to change the SEED status?
*

*>> Otherwise, the good estimations were obtained with RSE (10-20%) for the
*

*>> other parameters.
*

*>>
*

*>> *

*>> convergence for this setting of NBURN.
*

*>> "
*

*>> Convergence achieved
*

*>>
*

*>> STOCHASTIC PORTION WAS COMPLETED
*

*>> REDUCED STOCHASTIC PORTION WAS COMPLETED"
*

*>>
*

*>> Could you give me some instructions?
*

*>>
*

*>> Many thanks in advance for your responses.
*

*>> Best regards,
*

*>> Hai, LE Ba
*

*>> Ph.D Student
*

*>> La facultÃ© de Pharmacie - Aix Marseille universitÃ©
*

*>> Hanoi university of Pharmacy
*

*>> Email: lebahai01 *

*>> hailb *

*>> bahai.le *

*>>
*

*>>
*

*>> On Thu, Nov 5, 2020 at 10:43 AM Jakob Ribbing <
*

*>> jakob.ribbing *

*>>
*

*>>> Dear LE Ba,
*

*>>>
*

*>>> You did not share much information on your model, except that you have
*

*>>> one observations per subject and that EPS (or rather sigma) is estimate=
*

d (I

*>>> assume then a continuous endpoint).
*

*>>> Is thisyour only level of random effect, so that you have no omega/eta
*

*>>> for IOV or IIV? With one observations per subject it will be difficult =
*

to

*>>> find support for more than one level.
*

*>>> And for a model with only residual error (no IIV), would not the FO
*

*>>> Estimation method be sufficient, so why would you need to use SAEM for =
*

this

*>>> data/model?
*

*>>>
*

*>>> Best regards
*

*>>>
*

*>>> Jakob
*

*>>>
*

*>>>
*

*>>>
*

*>>> Jakob Ribbing, Ph.D.
*

*>>>
*

*>>> Senior Consultant, Pharmetheus AB
*

*>>>
*

*>>>
*

*>>> Cell/Mobile: +46 (0)70 514 33 77
*

*>>>
*

*>>> Jakob.Ribbing *

*>>>
*

*>>> www.pharmetheus.com
*

*>>>
*

*>>> Phone, Office: +46 (0)18 513 328
*

*>>>
*

*>>> Uppsala Science Park, Dag HammarskjÃ¶lds vÃ¤g 36B
*

*>>> SE-752 37 Uppsala, Sweden
*

*>>>
*

*>>>
*

*>>>
*

*>>> This communication is confidential and is only intended for the use of
*

*>>> the individual or entity to which it is directed. It may contain
*

*>>> information that is privileged and exempt from disclosure under applica=
*

ble

*>>> law. If you are not the intended recipient please notify us immediately=
*

.

*>>> Please do not copy it or disclose its contents to any other person.
*

*>>>
*

*>>>
*

*>>>
*

*>>>
*

*>>> On 5 Nov 2020, at 09:41, hai le ba <lebahai01 *

*>>>
*

*>>> Hello nmusers,
*

*>>> I've tried to test the SAEM method on my dataset (1 sample for each ID)
*

*>>> with different SEED status. Sometimes, I've got good results (with RSE
*

*>>> <50%), but sometimes I can't get it.
*

*>>>
*

*>>> Example:
*

*>>> $EST METHOD=SAEM INTERACTION NBURN=3000 NITER=500 AUTO=1 PRINT=
*

=100

*>>> SEED=123456789
*

*>>> $EST METHOD=IMP EONLY=1 PRINT=1 NITER=5 ISAMPLE=1000 MAPITER=
*

=0

*>>> I've got EPS : 0.00064 (RSE=63%)
*

*>>>
*

*>>> but
*

*>>> $EST METHOD=SAEM INTERACTION NBURN=3000 NITER=500 AUTO=1 PRINT=
*

=100

*>>> SEED=123235489
*

*>>> $EST METHOD=IMP EONLY=1 PRINT=1 NITER=5 ISAMPLE=1000 MAPITER=
*

=0

*>>> I've got EPS : 0.0223 (RSE=18%)
*

*>>>
*

*>>> Could i trust on the good results (EPS=0.0223)? How can we control th=
*

is

*>>> problem?
*

*>>>
*

*>>> Thank you very much,
*

*>>> Hai, LE Ba
*

*>>> Ph.D Student
*

*>>> La facultÃ© de Pharmacie - Aix Marseille universitÃ©
*

*>>> Hanoi university of Pharmacy
*

*>>> Email: lebahai01 *

*>>> hailb *

*>>> bahai.le *

*>>>
*

*>>>
*

*>>>
*

*>
*

Received on Thu Nov 05 2020 - 08:24:50 EST

Date: Thu, 5 Nov 2020 14:24:50 +0100

Yes, I totally agree with you. I have tested on the other kind of dataset

(more than 1 point per ID). All of the parameters are perfectly estimated.

Now, I'm trying to find an answer for the case of 1 PK point per each ID.

And, I have this problem with the number of seed options in the SAEM method=

.

Many thanks for your suggestion.

Hai, LE Ba

Ph.D Student

La facultÃ© de Pharmacie - Aix Marseille universitÃ©

Hanoi university of Pharmacy

Email: lebahai01

hailb

bahai.le

On Thu, Nov 5, 2020 at 1:05 PM Jakob Ribbing <jakob.ribbing

wrote:

ibutional

e

e

©crit :

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to

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.

=100

=0

=100

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is

Received on Thu Nov 05 2020 - 08:24:50 EST