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[NMusers] Modeling accelerated phase of malignancy

From: Mark Sale <msale_at_nuventra.com>
Date: Fri, 29 May 2015 19:52:36 +0000

Dear Colleagues,
  I'm working on a model of a malignancy that, at some point in the course =
of the disease enters into an accelerated phase. I'm using a sort of stand=
ard serial compartment model, with a zero order input rate, then first orde=
r transit to the next compartment. I think the "correct" model for natural=
 history is a slow increase in the input rate over time, then, at some poin=
t change to an exponential growth. I'm having trouble getting NONMEM to do=
 this. The relevant code I have in $DES is:

IF(T.LT.NTLAG) THEN
    LGIND = 0
ELSE
    LGIND = 1
END IF
NATHL = LGIND*NATH
DADT(3) = (INPUT-A(3)*K)+ A(3)*NATHL
DADT(4) = A(3)*K-A(4)*K
.
.
.
Where NTLAG is an estimated parameter for the lag time between entry into t=
he study and the onset of the accelerated phase, NATH is the natural histor=
y term, NATHL is the lagged natural history term, INPUT is the zero order i=
nput rate and K is the first order transit constant. FOCE actually works =
pretty well for this for the THETA term for NTLAG, gives reasonable values.=
  Probably is with the ETA for NTLAG (which is essential since it varies fr=
om person to person. With FOCE I get zero gradient for it. BAYES, SAEM, I=
MP MAP and ITS give reasonable values for OMEGA, but conditional values for=
 ETA are all zero.
What I think is going on is that, unlike an ALAG, there is not event at tha=
t point in time, so small changes in ETA (smaller than the integration step=
 size) don't change the predicted value, so no gradient and all ETAs = 0 =
with EM methods.
I've tried to figure out a way to do this with an additional compartment fo=
r the natural history and haven't been able to yet. That, I think would so=
lve the problem, since an event would be inserted at the end of ALAG.
Any ideas on a solution, is there a way to insert an event at an unknown ti=
me?

Thanks
Mark


Received on Fri May 29 2015 - 15:52:36 EDT

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