Re: [NMusers] Estimation method for ETAs with POSTHOC

[Ruben Faelens]

Dear Tingjie,

Your proposed objective function is based on least-squares distance. You
could also use the actual probability density:
objFunction = LOG(pnorm(Yobs - Ypred, sigma)) + LOG(pnorm(Para_i-Para_pop,
omega))
This allows more flexibility wrt parameter or residual variability
distributions.

I have previously implemented the above using the optim() function (with
Nelder-Mead method).

In my experience, the tricky part is making the prediction function robust.
Almost all optimization methods will evaluate widely varying values for the
parameters and expect a continuous OFV.
If you encounter numerical problems, you can always visualize the OFV to
gain a better understanding.

Finally, if you use this for dose recommendation, do not forget to evaluate
the uncertainty around the individual estimates! If you use an objective
function based on the actual log-likelihood, this is easy:
myHessian <- hessian(objFunction, etaEstimates)
FIM <- -1 * myHessian # Officially E(Hessian), but not necessary when using
numeric methods
myCovMatrix <- solve(FIM)

Good luck!

Kind regards,
Ruben Faelens

On Fri, May 5, 2017 at 2:17 PM Guo, Tingjie  wrote:

> Dear NMusers,
>
> I have two questions about the mathematical details on POSTHOC estimation
> in NONMEM. How does NONMEM actually do when doing POSTHOC ($EST METHOD=0
> MAXEVEL=0) to get ETAs? I assume but not for sure there is an objective
> function to be minimized, somewhat like:
>
>Objective function = SUM(Yobs-Ypred)^2/sigma^2 +
> SUM(Para_i-Para_pop)^2/omega^2
>
> Is there an objective function used in NONMEM when doing POSTHOC? If so,
> what is that function?
>
> Secondly, if the answer to above is yes, let’s assume the real objective
> function is the same as what I mentioned above. I wonder how (NONMEM does)
> to minimize this function? I am currently trying to do similar things in
> R/Python language. I tried Metropolis-Hasting algorithm and Simulated
> Annealing algorithm, but with some technical problems. And the result was
> not comparable with NONMEM as well. Can someone give me a direction for
> this? The more mathematically detailed the better.
>
> Thanks!
>
> Warm regards,
> Tingjie
>
>
>

[NMusers] Estimation method for ETAs with POSTHOC

[Guo, Tingjie]

Dear NMusers,

I have two questions about the mathematical details on POSTHOC estimation in 
NONMEM. How does NONMEM actually do when doing POSTHOC ($EST METHOD=0 
MAXEVEL=0) to get ETAs? I assume but not for sure there is an objective 
function to be minimized, somewhat like:
   
   Objective function = SUM(Yobs-Ypred)^2/sigma^2 + 
SUM(Para_i-Para_pop)^2/omega^2

Is there an objective function used in NONMEM when doing POSTHOC? If so, what 
is that function?

Secondly, if the answer to above is yes, let’s assume the real objective 
function is the same as what I mentioned above. I wonder how (NONMEM does) to 
minimize this function? I am currently trying to do similar things in R/Python 
language. I tried Metropolis-Hasting algorithm and Simulated Annealing 
algorithm, but with some technical problems. And the result was not comparable 
with NONMEM as well. Can someone give me a direction for this? The more 
mathematically detailed the better. 

Thanks!

Warm regards,
Tingjie

[NMusers] Exciting Range of Pharmacometrics Positions Within EU

[Ian Kulka]

Dear NMusers,

I am currently working a wide range of positions, suitable for experienced 
Pharmacometricians within  Europe. With a wide range of seniority and 
geographical options, please get in touch if any of these interest you.


Principal Pharmacometrician
Location: Germany  Salary: €100,000+
Are you an expert Pharmacometrician looking to join a global Pharmaceutical 
company at the Principal level? I am working with an industry leading company 
who are looking for principal scientists to join the team and utilise their 
expert knowledge within Pharmacometrics to provide unparalleled hands on 
support. Alongside being a hands on scientist you will play a key role in 
defining strategy for the group in regards to Pharmacometric support.

Principal Pharmacometrician
Location: Sweden   Salary: Highly competitive
I am working with a world leading pharmaceutical company who are looking for a 
Clinical Pharmacometrician to join the team. You will be working alongside 
other Clinical Pharmacometricans who work as part of larger interdisciplinary 
team who support clinical stage projects for the company. You will be working 
as a hands on expert but will also have the chance to mentor and guide more 
junior members of the team by passing on your mastery of Pharmacometrics

Senior Pharmacometrics Scientist
Location: United Kingdom Salary: Highly Competitive
I am working with a leading company in the heart of the scientific hub within 
the UK. You will working as part of a wider translational group and will 
provide expert Clinical Pharmacometric support to a number of innovative and 
exciting projects. You will need to have an expert understanding of NONMEM. as 
well as strong knowledge within a range of modelling techniques. As you will be 
joining a wider research group you will also have the unique opportunity to 
broaden your knowledge of the wider drug development process as you will be 
working closely with a range of interdisciplinary teams.

Principal Pharmacometric Scientist
Location: Belgium Salary: On application
I am working with an industry leading company who are currently looking for a 
Pharmacometrician to join the group.  You will be working as part of an expert 
team made of multiple disciplines, where you will  work on a number of area 
defining projects. You will be working as true hands in expert in the field so 
an advanced understanding of range of modelling techniques including, 
Population Modelling and exposure response analysis is required for this 
position.

Director Level Consulting Roles
Location: Flexible Salary: Highly Competitive
A highly successful,  worldwide healthcare provider is currently looking for 
experienced Pharmacometricans who might be interested in exploring the work 
within an exciting consultancy, at Principal/Director Level. You will have a 
diverse role, alongside the opportunity to work closely with various clients, 
interacting with ranging projects that span across multiple therapeutic areas 
and in various  stages of clinical development.

These are a brief highlight of some of the position I am working within Europe. 
If these do not match up to your requirements or expectations, then I would be 
more than happy to arrange a time to talk, and we can explore your industry 
options. If you could send me an updated CV, this will help to narrow down on 
the positions that could be applicable for you.

I look forward to hearing from you.

Warm regards,

Gareth
Gareth Howcroft
DMPK & Clinical Pharmacology Specialist Recruiter

Permanent and Contract
Specialist Recruitment

T: +44 (0)1293 584 300
E: gareth.howcr...@rbwconsulting.com
W: www.rbwconsulting.com