"""
:meta private:
"""
from __future__ import annotations
from typing import Literal
from pharmpy.basic import Expr
from pharmpy.model import (
Assignment,
Compartment,
CompartmentalSystem,
CompartmentalSystemBuilder,
Model,
Statements,
get_and_check_odes,
output,
)
from pharmpy.modeling import get_central_volume_and_clearance, set_initial_condition
from .error import set_proportional_error_model
from .odes import add_individual_parameter, set_initial_estimates
PDTypes = Literal['linear', 'emax', 'sigmoid', 'step', 'loglin']
[docs]
def add_effect_compartment(model: Model, expr: PDTypes):
r"""Add an effect compartment.
Implemented PD models are:
* Linear:
.. math:: E = B \cdot (1 + \text{slope} \cdot C)
* Emax:
.. math:: E = B \cdot \Bigg(1 + \frac {E_{max} \cdot C } { EC_{50} + C} \Bigg)
* Step effect:
.. math:: E = \Biggl \lbrace {B \quad \text{if C} \leq 0 \atop B \cdot (1+ E_{max}) \quad \text{else}}
* Sigmoidal:
.. math:: E=\Biggl \lbrace {B \cdot \Bigl(1+\frac{E_{max} \cdot C^n}{EC_{50}^n+C^n}\Bigl) \quad \
\text{if C}>0 \atop B \quad \text{else}}
* Log-linear:
.. math:: E = \text{slope} \cdot \text{log}(C + C_0)
:math:`B` is the baseline effect
Parameters
----------
model : Model
Pharmpy model
expr : {'linear', 'emax', 'sigmoid', 'step', 'loglin'}
Name of the PD effect function.
Return
------
Model
Pharmpy model object
Examples
--------
>>> from pharmpy.modeling import *
>>> model = load_example_model("pheno")
>>> model = add_effect_compartment(model, "linear")
>>> model.statements.ode_system.find_compartment("EFFECT")
Compartment(EFFECT, amount=A_EFFECT(t), input=KE0*A_CENTRAL(t)/VC)
"""
vc, cl = get_central_volume_and_clearance(model)
odes = get_and_check_odes(model)
central = odes.central_compartment
cb = CompartmentalSystemBuilder(odes)
ke0 = Expr.symbol("KE0")
met = Expr.symbol('MET')
model = add_individual_parameter(model, met.name)
ke0_ass = Assignment.create(ke0, 1 / met)
effect = Compartment.create("EFFECT", input=ke0 * central.amount / vc)
cb.add_compartment(effect)
cb.add_flow(effect, output, ke0)
model = model.replace(
statements=Statements(
model.statements.before_odes
+ ke0_ass
+ CompartmentalSystem(cb)
+ model.statements.after_odes
)
)
model = _add_effect(model, expr, effect.amount)
return model
[docs]
def set_direct_effect(model: Model, expr: PDTypes):
r"""Add an effect to a model.
Implemented PD models are:
* Linear:
.. math:: E = B \cdot (1 + \text{slope} \cdot C)
* Emax:
.. math:: E = B \cdot \Bigg(1 + \frac {E_{max} \cdot C } { EC_{50} + C} \Bigg)
* Step effect:
.. math:: E = \Biggl \lbrace {B \quad \text{if C} \leq 0 \atop B \cdot (1+ E_{max}) \quad \text{else}}
* Sigmoidal:
.. math:: E=\Biggl \lbrace {B \cdot \Bigl(1+\frac{E_{max} \cdot C^n}{EC_{50}^n+C^n}\Bigl) \quad \
\text{if C}>0 \atop B \quad \text{else}}
* Log-linear:
.. math:: E = \text{slope} \cdot \text{log}(C + C_0)
:math:`B` is the baseline effect
Parameters
----------
model : Model
Pharmpy model
expr : {'linear', 'emax', 'sigmoid', 'step', 'loglin'}
Name of PD effect function.
Return
------
Model
Pharmpy model object
Examples
--------
>>> from pharmpy.modeling import *
>>> model = load_example_model("pheno")
>>> model = set_direct_effect(model, "linear")
>>> model.statements.find_assignment("E")
⎛SLOPE⋅A_CENTRAL(t) ⎞
B⋅⎜────────────────── + 1⎟
E = ⎝ VC ⎠
"""
vc, cl = get_central_volume_and_clearance(model)
odes = get_and_check_odes(model)
conc = odes.central_compartment.amount / vc
model = _add_effect(model, expr, conc)
return model
def _add_effect(model: Model, expr: str, conc):
e0 = Expr.symbol("B")
model = add_individual_parameter(model, e0.name)
# Add effect E
if expr == "linear":
s = Expr.symbol("SLOPE")
model = add_individual_parameter(model, s.name)
E = Assignment(Expr.symbol('E'), e0 * (1 + (s * conc)))
elif expr == "emax":
emax = Expr.symbol("E_MAX")
model = add_individual_parameter(model, emax.name)
ec50 = Expr.symbol("EC_50")
model = add_individual_parameter(model, ec50.name)
E = Assignment(Expr.symbol("E"), e0 * (1 + (emax * conc / (ec50 + conc))))
elif expr == "step":
emax = Expr.symbol("E_MAX")
model = add_individual_parameter(model, emax.name)
E = Assignment(Expr.symbol("E"), Expr.piecewise((e0, conc <= 0), (e0 * (1 + emax), True)))
elif expr == "sigmoid":
emax = Expr.symbol("E_MAX")
model = add_individual_parameter(model, emax.name)
ec50 = Expr.symbol("EC_50")
model = add_individual_parameter(model, ec50.name)
n = Expr.symbol("N") # Hill coefficient
model = add_individual_parameter(model, n.name)
model = set_initial_estimates(model, {"POP_N": 1})
E = Assignment.create(
Expr.symbol("E"),
Expr.piecewise(
((e0 * (1 + (emax * conc**n / (ec50**n + conc**n)))), conc > 0), (e0, True)
),
)
elif expr == "loglin":
s = Expr.symbol("SLOPE")
model = add_individual_parameter(model, s.name)
E = Assignment(Expr.symbol("E"), s * (conc + (e0 / s).exp()).log())
else:
raise ValueError(f'Unknown model "{expr}".')
# Add dependent variable Y_2
y_2 = Expr.symbol('Y_2')
y = Assignment.create(y_2, E.symbol)
dvs = model.dependent_variables.replace(y_2, 2)
model = model.replace(statements=model.statements + E + y, dependent_variables=dvs)
# Add error model
model = set_proportional_error_model(model, dv=2, zero_protection=False)
return model
[docs]
def add_indirect_effect(
model: Model,
expr: Literal['linear', 'emax', 'sigmoid', 'step'],
prod: bool = True,
):
r"""Add indirect (turnover) effect
The concentration :math:`C_c` has an impact on the production or degradation rate of the response R:
* Production:
.. math:: \frac {dR}{dt} = k_{in} \cdot (1 + f(C_c)) - k_{out} \cdot R
* Degradation:
.. math:: \frac {dR}{dt} = k_{in} - k_{out} \cdot (1 + f(C_c)) \cdot R
:math:`k_{in}` and :math:`k_{out}` can either be inhibited or stimulated.
Baseline :math:`B = R(0) = R_0 = k_{in}/k_{out}`.
Models:
* Linear:
.. math:: f(C_c) = \text{slope} \cdot C_c
* Emax:
.. math:: f(C_c) = \frac {E_{max} \cdot C_c } { EC_{50} + C_c }
* Sigmoidal:
.. math:: f(C_c) = \frac{E_{max} \cdot C_c^n}{EC_{50}^n+C^n}
Parameters
----------
model : Model
Pharmpy model
prod : bool
Production (True) (default) or degradation (False)
expr : {'linear', 'emax', 'sigmoid', 'step'}
Name of PD effect function.
Return
------
Model
Pharmpy model object
Examples
--------
>>> from pharmpy.modeling import *
>>> model = load_example_model("pheno")
>>> model = add_indirect_effect(model, expr='linear', prod=True)
"""
vc, cl = get_central_volume_and_clearance(model)
odes = get_and_check_odes(model)
central = odes.central_compartment
conc_c = central.amount / vc
response = Compartment.create("RESPONSE")
a_response = response.amount
kin = Expr.symbol("K_IN")
kout = Expr.symbol("K_OUT")
met = Expr.symbol('MET')
model = add_individual_parameter(model, met.name)
b = Expr.symbol("B") # baseline
model = add_individual_parameter(model, b.name)
kout_ass = Assignment.create(kout, 1 / met)
kin_ass = Assignment.create(kin, kout * b)
if expr == 'linear':
s = Expr.symbol("SLOPE")
model = add_individual_parameter(model, s.name)
R = Expr.symbol("SLOPE") * conc_c
elif expr == 'emax':
emax = Expr.symbol("E_MAX")
model = add_individual_parameter(model, emax.name)
ec50 = Expr.symbol("EC_50")
model = add_individual_parameter(model, ec50.name)
R = emax * conc_c / (ec50 + conc_c)
elif expr == 'sigmoid':
emax = Expr.symbol("E_MAX")
ec50 = Expr.symbol("EC_50")
n = Expr.symbol("N")
model = add_individual_parameter(model, n.name)
model = set_initial_estimates(model, {"POP_N": 1})
model = add_individual_parameter(model, ec50.name)
model = add_individual_parameter(model, emax.name)
R = emax * conc_c**n / (ec50**n + conc_c**n)
else:
raise ValueError(f'Unknown model "{expr}".')
cb = CompartmentalSystemBuilder(odes)
if prod:
response = Compartment.create("RESPONSE", input=kin * (1 + R))
cb.add_compartment(response)
cb.add_flow(response, output, kout)
elif not prod:
response = Compartment.create("RESPONSE", input=kin)
cb.add_compartment(response)
cb.add_flow(response, output, kout * (1 + R))
model = model.replace(
statements=Statements(
model.statements.before_odes
+ kout_ass
+ kin_ass
+ CompartmentalSystem(cb)
+ model.statements.after_odes
)
)
model = set_initial_condition(model, "RESPONSE", b)
# Add dependent variable Y_2
y_2 = Expr.symbol('Y_2')
y = Assignment(y_2, a_response)
dvs = model.dependent_variables.replace(y_2, 2)
model = model.replace(statements=model.statements + y, dependent_variables=dvs)
# Add error model
model = set_proportional_error_model(model, dv=2, zero_protection=False)
return model.update_source()
[docs]
def set_baseline_effect(model: Model, expr: str = 'const'):
r"""Create baseline effect model.
Currently implemented baseline effects are:
Constant baseline effect (const):
.. math:: E = B
Parameters
----------
model : Model
Pharmpy model
expr : str
Name of baseline effect function.
Return
------
Model
Pharmpy model object
Examples
--------
>>> from pharmpy.modeling import *
>>> model = load_example_model("pheno")
>>> model = set_baseline_effect(model, expr='const')
>>> model.statements.find_assignment("E")
E = B
"""
e0 = Expr.symbol("B")
model = add_individual_parameter(model, e0.name)
E = Assignment(Expr.symbol('E'), e0)
# Add dependent variable Y_2
y_2 = Expr.symbol('Y_2')
y = Assignment.create(y_2, E.symbol)
dvs = model.dependent_variables.replace(y_2, 2)
model = model.replace(statements=model.statements + E + y, dependent_variables=dvs)
# Add error model
model = set_proportional_error_model(model, dv=2, zero_protection=False)
return model
