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From: Mark Sale <msale_at_nuventra.com>

Date: Sat, 20 Feb 2016 20:01:50 +0000

Matts,

Thanks for your insights. But, the issue isn't the post hoc values. W=

ith the mixture model the OMEGA on the intercept is huge (680), and the ent=

ire population is in the low intercept value group (Intercept = -11). Th=

en to accommodate the patients with frequent AEs, it assigns a (post hoc) E=

TA of +15, giving an individual value for intercept of 6 (and a probability=

of the AE of ~1, as it should. My question is whey does it refuse to simp=

ly put those 8% of the patients in a sub population with intercept = 6, E=

TA=0. rather than saying the expected value is -11, with ETA = +15. Eve=

n when I fix the fractions in the subpopulations for the observed values, a=

nd fix OMEGA to a small, reasonable value, and fix the intercept values f=

or the 3 populations to reasonable values it will still do this. The only =

thing that has worked is to assign each subject to the apparent population =

in the data set.

Mark

Mark Sale M.D.

Vice President, Modeling and Simulation

Nuventra, Inc. ™

2525 Meridian Parkway, Suite 280

Research Triangle Park, NC 27713

Office (919)-973-0383

msale_at_nuventra.com<msale_at_kinetigen.com>

www.nuventra.com<http://www.nuventra.com>

Empower your Pipeline

CONFIDENTIALITY NOTICE The information in this transmittal (including attac=

hments, if any) may be privileged and confidential and is intended only for=

the recipient(s) listed above. Any review, use, disclosure, distribution o=

r copying of this transmittal, in any form, is prohibited except by or on b=

ehalf of the intended recipient(s). If you have received this transmittal i=

n error, please notify me immediately by reply email and destroy all copies=

of the transmittal.

________________________________

From: Matts Kågedal <mattskagedal_at_gmail.com>

Sent: Saturday, February 20, 2016 2:44 PM

To: Mark Sale

Cc: nmusers_at_globomaxnm.com

Subject: Re: [NMusers] Mixture model with logistic regression

Hi Mark,

The pattern you see in the posthocs could possibly be a shrinkage phenomeno=

n. I.e. patients with AE most of the time will have the same ETA, while pat=

ients with no AE will have the same ETA and there will be a third group in =

between. If shrinkage is causing this, you should not expect any improveme=

nt with a mixture model. Before you reject your original model I would ther=

efore also evaluate it by simulation and re-estimation. I think it is quite=

possible that you will retreive a similar pattern in the posthocs even whe=

n you simulate based on a normal distribution.

Best,

Matts Kågedal

Pharmacometrics, Genentech.

On Fri, Feb 19, 2016 at 2:30 PM, Mark Sale <msale_at_nuventra.com<mailto:msale=

_at_nuventra.com>> wrote:

Has anyone every tried to use a mixture model with logistic regression? I h=

ave data on a AE in several hundred patients, measured multiple times (10-2=

0 times per patient). Examining the data it is clear that, independent of =

drug concentration, there is very wide distribution of this AE, 68% of the =

patients never have the AE, 25% have it about 20% of the time and the rest =

have it pretty much continuously, regardless of drug concentration. (in or=

dinary logistic regression, just glm in R, there is also a nice concentrati=

on effect on the AE in addition). Running the usual logistic model, not s=

urprisingly, I get a really big ETA on the intercept, with 68% of the peopl=

e having ETA small negative, 25% ETA ~ 1 and 7% ETA ~ 10. No covariates see=

m particularly predictive of the post hoc ETA. I thought I could use a mix=

ture model, with 3 modes, but it refused to do that, giving me essentially =

0% in the 2nd and 3rd distribution, still with the really large OMEGA for t=

he intercept. Even when I FIX the OMEGA to a reasonable number, I still ge=

t essentially no one in the 2nd and 3rd distribution. I tried fixing the f=

raction in the 2nd and 3rd distribution (and OMEGA), and it still gave me a=

very small difference in the intercept for the 2nd and 3rd populations.

Is there an issue with using mixture models with logistic regression? I'm j=

ust using FOCE, Laplacian, without interaction, and LIKE.

Any ideas?

Mark

Mark Sale M.D.

Vice President, Modeling and Simulation

Nuventra, Inc. ™

2525 Meridian Parkway, Suite 280

Research Triangle Park, NC 27713

Office (919)-973-0383<tel:%28919%29-973-0383>

msale_at_nuventra.com<http://msale_at_kinetigen.com>

www.nuventra.com<http://www.nuventra.com>

Received on Sat Feb 20 2016 - 15:01:50 EST

Date: Sat, 20 Feb 2016 20:01:50 +0000

Matts,

Thanks for your insights. But, the issue isn't the post hoc values. W=

ith the mixture model the OMEGA on the intercept is huge (680), and the ent=

ire population is in the low intercept value group (Intercept = -11). Th=

en to accommodate the patients with frequent AEs, it assigns a (post hoc) E=

TA of +15, giving an individual value for intercept of 6 (and a probability=

of the AE of ~1, as it should. My question is whey does it refuse to simp=

ly put those 8% of the patients in a sub population with intercept = 6, E=

TA=0. rather than saying the expected value is -11, with ETA = +15. Eve=

n when I fix the fractions in the subpopulations for the observed values, a=

nd fix OMEGA to a small, reasonable value, and fix the intercept values f=

or the 3 populations to reasonable values it will still do this. The only =

thing that has worked is to assign each subject to the apparent population =

in the data set.

Mark

Mark Sale M.D.

Vice President, Modeling and Simulation

Nuventra, Inc. ™

2525 Meridian Parkway, Suite 280

Research Triangle Park, NC 27713

Office (919)-973-0383

msale_at_nuventra.com<msale_at_kinetigen.com>

www.nuventra.com<http://www.nuventra.com>

Empower your Pipeline

CONFIDENTIALITY NOTICE The information in this transmittal (including attac=

hments, if any) may be privileged and confidential and is intended only for=

the recipient(s) listed above. Any review, use, disclosure, distribution o=

r copying of this transmittal, in any form, is prohibited except by or on b=

ehalf of the intended recipient(s). If you have received this transmittal i=

n error, please notify me immediately by reply email and destroy all copies=

of the transmittal.

________________________________

From: Matts Kågedal <mattskagedal_at_gmail.com>

Sent: Saturday, February 20, 2016 2:44 PM

To: Mark Sale

Cc: nmusers_at_globomaxnm.com

Subject: Re: [NMusers] Mixture model with logistic regression

Hi Mark,

The pattern you see in the posthocs could possibly be a shrinkage phenomeno=

n. I.e. patients with AE most of the time will have the same ETA, while pat=

ients with no AE will have the same ETA and there will be a third group in =

between. If shrinkage is causing this, you should not expect any improveme=

nt with a mixture model. Before you reject your original model I would ther=

efore also evaluate it by simulation and re-estimation. I think it is quite=

possible that you will retreive a similar pattern in the posthocs even whe=

n you simulate based on a normal distribution.

Best,

Matts Kågedal

Pharmacometrics, Genentech.

On Fri, Feb 19, 2016 at 2:30 PM, Mark Sale <msale_at_nuventra.com<mailto:msale=

_at_nuventra.com>> wrote:

Has anyone every tried to use a mixture model with logistic regression? I h=

ave data on a AE in several hundred patients, measured multiple times (10-2=

0 times per patient). Examining the data it is clear that, independent of =

drug concentration, there is very wide distribution of this AE, 68% of the =

patients never have the AE, 25% have it about 20% of the time and the rest =

have it pretty much continuously, regardless of drug concentration. (in or=

dinary logistic regression, just glm in R, there is also a nice concentrati=

on effect on the AE in addition). Running the usual logistic model, not s=

urprisingly, I get a really big ETA on the intercept, with 68% of the peopl=

e having ETA small negative, 25% ETA ~ 1 and 7% ETA ~ 10. No covariates see=

m particularly predictive of the post hoc ETA. I thought I could use a mix=

ture model, with 3 modes, but it refused to do that, giving me essentially =

0% in the 2nd and 3rd distribution, still with the really large OMEGA for t=

he intercept. Even when I FIX the OMEGA to a reasonable number, I still ge=

t essentially no one in the 2nd and 3rd distribution. I tried fixing the f=

raction in the 2nd and 3rd distribution (and OMEGA), and it still gave me a=

very small difference in the intercept for the 2nd and 3rd populations.

Is there an issue with using mixture models with logistic regression? I'm j=

ust using FOCE, Laplacian, without interaction, and LIKE.

Any ideas?

Mark

Mark Sale M.D.

Vice President, Modeling and Simulation

Nuventra, Inc. ™

2525 Meridian Parkway, Suite 280

Research Triangle Park, NC 27713

Office (919)-973-0383<tel:%28919%29-973-0383>

msale_at_nuventra.com<http://msale_at_kinetigen.com>

www.nuventra.com<http://www.nuventra.com>

Received on Sat Feb 20 2016 - 15:01:50 EST

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