scikit-complexity 0.2.0__py3-none-any.whl

skcomplex/models/biology/oncology/_hormone_therapy.py

@@ -0,0 +1,985 @@
+"""Oncology models: prostate and breast cancers under hormone therapy."""
+
+# Author: Georgios Douzas <gdouzas@icloud.com>
+# License: MIT
+
+from collections.abc import Callable
+from types import SimpleNamespace
+
+from sage.all__sagemath_symbolics import Expression, log
+
+from ....core.interactions import BaseInteraction, RateInteraction, ReactionInteraction
+from ....core.laws.utils import hill, pulse_train
+from ....core.system import System
+from ....engine.solvers import ScipyODESolver
+from ....errors import ValidationError
+from ..._catalog import register_model
+from ..common.pharmacokinetics import DosingInteraction
+from ._androgen_receptor_prostate import AndrogenReceptorProstateElement
+from ._androgen_suppression import AndrogenSuppressionElement
+from ._cell_quota_prostate import CellQuotaProstateElement
+from ._intermittent_suppression import IntermittentSuppressionElement
+from ._piecewise_linear_prostate import PiecewiseLinearProstateElement
+from ._tamoxifen_tumour import TamoxifenTumourElement
+from ._therapy_switch import TherapySwitchInteraction
+
+BOOK = 'Padmanabhan, Meskin, and Al Moustafa 2021'
+
+
+PATIENT_FACTORS = {
+    1: {
+        'on': (0.956156, 0.00130716, 0.995718, 0.0, 0.0, 1.00181),
+        'off': (1.00223, 0.1, 1.00392, 0.8),
+        'cells': (17.84, 0.778, 0.382),
+    },
+    2: {
+        'on': (0.925733, 0.00737385, 0.990242, 0.000130721, 0.0, 1.00339),
+        'off': (1.00089, 0.1, 1.00147, 1.00079),
+        'cells': (13.43, 1.57, 0.0),
+    },
+    3: {
+        'on': (0.931568, 0.0, 0.992614, 0.00083635, 0.0, 1.00242),
+        'off': (1.00306, 0.1, 1.0025, 1.00282),
+        'cells': (11.02, 0.976, 0.0),
+    },
+}
+
+
+def _prostate_volume(target: SimpleNamespace, t: Expression) -> Expression:
+    """Return the prostate volume in cm³ at the age of the patient, `v1 a^phi / (v2^phi + a^phi) + v3`."""
+    age = target.age + t / 8760
+    volume: Expression = target.v1 * age**target.phi / (target.v2**target.phi + age**target.phi) + target.v3
+    return volume
+
+
+def _receptor_growth(target: SimpleNamespace, psi1: Expression, phi1: Expression) -> Expression:
+    """Return the growth rate that the receptors activated by DHT and testosterone drive."""
+    UD, UT = target.UD, target.UT
+    growth: Expression = psi1 * UD**2 / (target.psi2**2 + UD**2) + phi1 * UT**2 / (target.phi2**2 + UT**2)
+    return growth
+
+
+def _receptor_death(target: SimpleNamespace, psi3: Expression) -> Expression:
+    """Return the death rate that the activated receptors lower."""
+    death: Expression = psi3 / (target.psi4 + target.UD + target.UT)
+    return death
+
+
+def _dependent_division(target: SimpleNamespace) -> Expression:
+    """Return the division of androgen-dependent cells, crowded by the normal and the cancer cells."""
+    crowding = (target.c1 * target.N + target.AD + target.AI) / target.b2
+    division: Expression = _receptor_growth(target, target.psi1_d, target.phi1_d) * target.AD * (1 - crowding)
+    return division
+
+
+def _quota_uptake(target: SimpleNamespace, Q: Expression, q: Expression) -> Expression:
+    """Return the uptake of androgen into a quota, which slows as the quota fills."""
+    uptake: Expression = target.vm * (target.qm - Q) / (target.qm - q) * target.U / (target.U + target.v50)
+    return uptake
+
+
+def _room(target: SimpleNamespace) -> Expression:
+    """Return the Gompertz room `log(Asat / (Ag + As + Am))` that slows the passage through the cell cycle."""
+    room: Expression = log(target.Asat / (target.Ag + target.As + target.Am))
+    return room
+
+
+def _get_switches(signal: Callable[[SimpleNamespace], object], h0: float, h1: float) -> list[BaseInteraction]:
+    """Return the relay with hysteresis that starts the therapy above `h1` and stops it below `h0` of a signal."""
+    return [
+        TherapySwitchInteraction('on', target='tumour', signal=signal, threshold=h1, value=1.0, direction=1),
+        TherapySwitchInteraction('off', target='tumour', signal=signal, threshold=h0, value=0.0, direction=-1),
+    ]
+
+
+@register_model(
+    field='biology/oncology',
+    tags=('hormone therapy', 'ode', 'prostate cancer', 'androgen'),
+    references=(BOOK, 'Zazoua and Wang 2019'),
+    defaults={'until': 1500.0, 'dt': 5.0},
+)
+def continuous_androgen_suppression(
+    AD: float = 10.0,
+    AI: float = 0.14,
+    U: float = 20.0,
+    *,
+    r1: float = 0.025,
+    r2: float = 0.006,
+    b: float = 0.091e-9,
+    c1: float = 0.9,
+    c2: float = 0.8,
+    d1: float = 0.064,
+    m1: float = 5e-5,
+    U0: float = 20.0,
+    du: float = 0.08,
+    a: float = 0.9,
+) -> System:
+    """Return prostate cancer under continuous androgen suppression, which androgen-independent cells survive.
+
+    The suppression lowers the serum androgen from `U0` to `U0 (1 - a)` at the rate `du`. The androgen-dependent cells
+    grow in proportion to the androgen and die and turn independent in proportion to the deprivation `1 - U / U0`, so
+    they decline once the suppression is deep enough, while the independent cells grow regardless and cause the
+    relapse. Cells are counted, androgen is in ng/mL, and time is in days. The book's efficacy lies between 0.6 and
+    0.9, and only the upper end makes the dependent cells decline.
+
+    Args:
+        AD:
+            The initial androgen-dependent cells.
+
+        AI:
+            The initial androgen-independent cells.
+
+        U:
+            The initial serum androgen.
+
+        r1:
+            The growth rate of the dependent cells per unit of androgen.
+
+        r2:
+            The growth rate of the independent cells.
+
+        b:
+            The reciprocal carrying capacity.
+
+        c1:
+            The competition of the independent cells on the dependent ones.
+
+        c2:
+            The competition of the dependent cells on the independent ones.
+
+        d1:
+            The death rate of the dependent cells under androgen deprivation.
+
+        m1:
+            The rate at which androgen deprivation turns dependent cells independent.
+
+        U0:
+            The normal androgen concentration.
+
+        du:
+            The elimination rate of the androgen.
+
+        a:
+            The efficacy of the suppression.
+
+    Returns:
+        system:
+            The model, with the cells `tumour.AD` and `tumour.AI` and the androgen `tumour.U`.
+
+    Examples:
+        >>> from skcomplex.models.biology.oncology import continuous_androgen_suppression
+        >>> continuous_androgen_suppression(a=0.6).elements[0].a
+        0.6
+    """
+    tumour = AndrogenSuppressionElement(
+        'tumour',
+        AD=AD,
+        AI=AI,
+        U=U,
+        r1=r1,
+        r2=r2,
+        b=b,
+        c1=c1,
+        c2=c2,
+        d1=d1,
+        m1=m1,
+        U0=U0,
+        du=du,
+        a=a,
+    )
+    interactions = [
+        RateInteraction(
+            'dependent_growth',
+            target='tumour',
+            state='AD',
+            rate=lambda s: s.target.r1
+            * s.target.U
+            * (1 - s.target.b * (s.target.AD + s.target.c1 * s.target.AI))
+            * s.target.AD,
+        ),
+        ReactionInteraction(
+            'deprivation_death',
+            target='tumour',
+            reactants={'AD': 1},
+            propensity=lambda s: s.target.d1 * (1 - s.target.U / s.target.U0) * s.target.AD,
+        ),
+        ReactionInteraction(
+            'mutation',
+            target='tumour',
+            reactants={'AD': 1},
+            products={'AI': 1},
+            propensity=lambda s: s.target.m1 * (1 - s.target.U / s.target.U0) * s.target.AD,
+        ),
+        RateInteraction(
+            'independent_growth',
+            target='tumour',
+            state='AI',
+            rate=lambda s: s.target.r2 * (1 - s.target.b * (s.target.AI + s.target.c2 * s.target.AD)) * s.target.AI,
+        ),
+        RateInteraction(
+            'androgen_production',
+            target='tumour',
+            state='U',
+            rate=lambda s: -s.target.du * (s.target.U - s.target.U0),
+        ),
+        RateInteraction(
+            'suppression',
+            target='tumour',
+            state='U',
+            rate=lambda s: -s.target.U0 * s.target.du * s.target.a,
+        ),
+    ]
+    return System(elements=[tumour], interactions=interactions)
+
+
+@register_model(
+    field='biology/oncology',
+    tags=('hormone therapy', 'ode', 'prostate cancer', 'events', 'intermittent'),
+    references=(BOOK, 'Ideta et al. 2008'),
+    defaults={'until': 600.0, 'dt': 2.0},
+)
+def ideta_intermittent_androgen(
+    AD: float = 5.0,
+    AI: float = 0.0,
+    *,
+    r1: float = 0.0204,
+    r2: float = 0.0242,
+    d1: float = 0.0076,
+    d2: float = 0.0168,
+    m1: float = 5e-5,
+    k1: float = 0.0,
+    k2: float = 2.0,
+    k3: float = 8.0,
+    k4: float = 0.5,
+    U0: float = 30.0,
+    du: float = 0.08,
+    h0: float = 10.0,
+    h1: float = 15.0,
+) -> System:
+    """Return the Ideta model of intermittent androgen suppression, switched on and off by PSA thresholds.
+
+    The therapy starts when the serum PSA, the number of cancer cells, rises through `h1` and stops when it falls
+    through `h0`. The androgen follows with the delay `1 / du`, so the dependent cells shrink during therapy and regrow
+    after it, and the PSA cycles between the thresholds while the independent cells stay few. Cells are counted, the
+    PSA is in ng/mL, the androgen in nmol/L, starting at its normal level `U0` within the book's 8 to 35, and time is
+    in days.
+
+    Args:
+        AD:
+            The initial androgen-dependent cells.
+
+        AI:
+            The initial androgen-independent cells.
+
+        r1:
+            The growth rate of the dependent cells.
+
+        r2:
+            The growth rate of the independent cells.
+
+        d1:
+            The death rate of the dependent cells.
+
+        d2:
+            The death rate of the independent cells.
+
+        m1:
+            The maximum rate at which dependent cells turn independent.
+
+        k1:
+            The growth of the dependent cells without androgen, relative to `r1`.
+
+        k2:
+            The androgen at which the growth of the dependent cells is half way.
+
+        k3:
+            The death of the dependent cells without androgen, relative to `d1`.
+
+        k4:
+            The androgen at which the death of the dependent cells is half way.
+
+        U0:
+            The normal androgen concentration.
+
+        du:
+            The elimination rate of the androgen.
+
+        h0:
+            The PSA below which the therapy stops.
+
+        h1:
+            The PSA above which the therapy starts.
+
+    Returns:
+        system:
+            The model, with the cells `tumour.AD` and `tumour.AI`, the androgen `tumour.U`, the therapy `tumour.u`, and
+            the switches as `on` and `off` events.
+
+    Examples:
+        >>> from skcomplex.models.biology.oncology import ideta_intermittent_androgen
+        >>> ideta_intermittent_androgen(h1=20.0).interactions[-2].threshold
+        20.0
+    """
+    tumour = IntermittentSuppressionElement(
+        'tumour',
+        AD=AD,
+        AI=AI,
+        U=U0,
+        r1=r1,
+        r2=r2,
+        d1=d1,
+        d2=d2,
+        m1=m1,
+        k1=k1,
+        k2=k2,
+        k3=k3,
+        k4=k4,
+        U0=U0,
+        du=du,
+    )
+    switches = _get_switches(lambda s: s.target.x1 * s.target.AD + s.target.x2 * s.target.AI, h0, h1)
+    interactions = [
+        RateInteraction(
+            'dependent_growth',
+            target='tumour',
+            state='AD',
+            rate=lambda s: s.target.r1
+            * (s.target.k1 + (1 - s.target.k1) * s.target.U / (s.target.U + s.target.k2))
+            * s.target.AD,
+        ),
+        ReactionInteraction(
+            'dependent_death',
+            target='tumour',
+            reactants={'AD': 1},
+            propensity=lambda s: s.target.d1
+            * (s.target.k3 + (1 - s.target.k3) * s.target.U / (s.target.U + s.target.k4))
+            * s.target.AD,
+        ),
+        ReactionInteraction(
+            'mutation',
+            target='tumour',
+            reactants={'AD': 1},
+            products={'AI': 1},
+            propensity=lambda s: s.target.m1 * (1 - s.target.U / s.target.U0) * s.target.AD,
+        ),
+        RateInteraction(
+            'independent_growth',
+            target='tumour',
+            state='AI',
+            rate=lambda s: s.target.r2 * (1 - s.target.U / s.target.U0) * s.target.AI,
+        ),
+        ReactionInteraction(
+            'independent_death',
+            target='tumour',
+            reactants={'AI': 1},
+            propensity=lambda s: s.target.d2 * s.target.AI,
+        ),
+        RateInteraction(
+            'androgen_production',
+            target='tumour',
+            state='U',
+            rate=lambda s: -s.target.du * (s.target.U - s.target.U0),
+        ),
+        RateInteraction(
+            'suppression',
+            target='tumour',
+            state='U',
+            rate=lambda s: -s.target.U0 * s.target.du * s.target.u,
+        ),
+        *switches,
+    ]
+    return System(elements=[tumour], interactions=interactions)
+
+
+@register_model(
+    field='biology/oncology',
+    tags=('hormone therapy', 'ode', 'prostate cancer', 'cell quota', 'intermittent'),
+    references=(BOOK, 'Portz, Kuang, and Nagy 2012'),
+    defaults={'until': 1500.0, 'dt': 5.0},
+)
+def prostate_cell_quota(
+    AD: float = 15.0,
+    AI: float = 0.0,
+    *,
+    rm: float = 0.025,
+    q1: float = 0.3,
+    q2: float = 0.15,
+    d1: float = 0.015,
+    d2: float = 0.015,
+    r0: float = 0.01,
+    r1: float = 0.15,
+    r2: float = 0.15,
+    n: float = 3.0,
+    theta: float = 3.0,
+    U0: float = 15.0,
+    Umin: float = 0.5,
+    du1: float = 0.08,
+    period: float = 500.0,
+    width: float = 250.0,
+) -> System:
+    """Return the Portz cell-quota model of prostate cancer, whose cells grow on their internal androgen.
+
+    The androgen-dependent and independent cells grow at the Droop rate `rm (1 - q_i / Q_i)` of their cell quotas,
+    which take up serum androgen, and the PSA they release follows the quotas. A deprived dependent cell turns
+    independent faster, and an independent cell full of androgen turns back. The serum androgen follows the
+    exponential relaxation of the book's equation 7.18 between the normal level `U0` and `Umin`, with therapy during
+    the first `width` days of every `period`. The book gives neither the steepness `n` of the mutation rates nor
+    `theta` of the PSA production, nor the serum levels, their relaxation rate, and the schedule, so these defaults
+    are chosen, and the other defaults lie within the book's ranges. Cells are in billions, quotas in nM, PSA in
+    ng/mL, and time in days. The PSA starts near its value for the initial quotas.
+
+    Args:
+        AD:
+            The initial androgen-dependent cells.
+
+        AI:
+            The initial androgen-independent cells.
+
+        rm:
+            The maximum proliferation rate.
+
+        q1:
+            The minimum quota of the dependent cells.
+
+        q2:
+            The minimum quota of the independent cells.
+
+        d1:
+            The death rate of the dependent cells.
+
+        d2:
+            The death rate of the independent cells.
+
+        r0:
+            The baseline PSA production per cell.
+
+        r1:
+            The androgen-driven PSA production per dependent cell.
+
+        r2:
+            The androgen-driven PSA production per independent cell.
+
+        n:
+            The steepness of the mutation rates.
+
+        theta:
+            The steepness of the PSA production.
+
+        U0:
+            The normal serum androgen.
+
+        Umin:
+            The serum androgen under therapy.
+
+        du1:
+            The rate at which the serum androgen relaxes.
+
+        period:
+            The time between the starts of therapy periods.
+
+        width:
+            The duration of a therapy period.
+
+    Returns:
+        system:
+            The model, with the cells `tumour.AD` and `tumour.AI`, the quotas `tumour.Q1` and `tumour.Q2`, the PSA
+            `tumour.P`, and the androgen `tumour.U`.
+
+    Examples:
+        >>> from skcomplex.models.biology.oncology import prostate_cell_quota
+        >>> prostate_cell_quota(q1=0.45).elements[0].q1
+        0.45
+    """
+    tumour = CellQuotaProstateElement(
+        'tumour',
+        AD=AD,
+        AI=AI,
+        U=U0,
+        rm=rm,
+        q1=q1,
+        q2=q2,
+        d1=d1,
+        d2=d2,
+        r0=r0,
+        r1=r1,
+        r2=r2,
+        n=n,
+        theta=theta,
+        U0=U0,
+        Umin=Umin,
+        du1=du1,
+        period=period,
+        width=width,
+    )
+    interactions = [
+        RateInteraction(
+            'dependent_growth',
+            target='tumour',
+            state='AD',
+            rate=lambda s: s.target.rm * (1 - s.target.q1 / s.target.Q1) * s.target.AD,
+        ),
+        ReactionInteraction(
+            'dependent_death',
+            target='tumour',
+            reactants={'AD': 1},
+            propensity=lambda s: s.target.d1 * s.target.AD,
+        ),
+        ReactionInteraction(
+            'to_independent',
+            target='tumour',
+            reactants={'AD': 1},
+            products={'AI': 1},
+            propensity=lambda s: s.target.mx1 * (1 - hill(s.target.Q1, s.target.m501, s.target.n)) * s.target.AD,
+        ),
+        ReactionInteraction(
+            'to_dependent',
+            target='tumour',
+            reactants={'AI': 1},
+            products={'AD': 1},
+            propensity=lambda s: s.target.mx2 * hill(s.target.Q2, s.target.m502, s.target.n) * s.target.AI,
+        ),
+        RateInteraction(
+            'independent_growth',
+            target='tumour',
+            state='AI',
+            rate=lambda s: s.target.rm * (1 - s.target.q2 / s.target.Q2) * s.target.AI,
+        ),
+        ReactionInteraction(
+            'independent_death',
+            target='tumour',
+            reactants={'AI': 1},
+            propensity=lambda s: s.target.d2 * s.target.AI,
+        ),
+        RateInteraction(
+            'dependent_uptake',
+            target='tumour',
+            state='Q1',
+            rate=lambda s: _quota_uptake(s.target, s.target.Q1, s.target.q1),
+        ),
+        RateInteraction(
+            'dependent_use',
+            target='tumour',
+            state='Q1',
+            rate=lambda s: -s.target.rm * (s.target.Q1 - s.target.q1),
+        ),
+        ReactionInteraction(
+            'dependent_degradation',
+            target='tumour',
+            reactants={'Q1': 1},
+            propensity=lambda s: s.target.d3 * s.target.Q1,
+        ),
+        RateInteraction(
+            'independent_uptake',
+            target='tumour',
+            state='Q2',
+            rate=lambda s: _quota_uptake(s.target, s.target.Q2, s.target.q2),
+        ),
+        RateInteraction(
+            'independent_use',
+            target='tumour',
+            state='Q2',
+            rate=lambda s: -s.target.rm * (s.target.Q2 - s.target.q2),
+        ),
+        ReactionInteraction(
+            'independent_degradation',
+            target='tumour',
+            reactants={'Q2': 1},
+            propensity=lambda s: s.target.d3 * s.target.Q2,
+        ),
+        RateInteraction(
+            'psa_leak',
+            target='tumour',
+            state='P',
+            rate=lambda s: s.target.r0 * (s.target.AD + s.target.AI),
+        ),
+        RateInteraction(
+            'psa_production',
+            target='tumour',
+            state='P',
+            rate=lambda s: s.target.r1 * s.target.AD * hill(s.target.Q1, s.target.rho1, s.target.theta)
+            + s.target.r2 * s.target.AI * hill(s.target.Q2, s.target.rho2, s.target.theta),
+        ),
+        ReactionInteraction(
+            'psa_clearance',
+            target='tumour',
+            reactants={'P': 1},
+            propensity=lambda s: s.target.du * s.target.P,
+        ),
+        RateInteraction(
+            'androgen',
+            target='tumour',
+            state='U',
+            rate=lambda s: s.target.du1
+            * (
+                s.target.U0 - (s.target.U0 - s.target.Umin) * pulse_train(s.t, tumour.period, tumour.width) - s.target.U
+            ),
+        ),
+    ]
+    return System(elements=[tumour], interactions=interactions)
+
+
+@register_model(
+    field='biology/oncology',
+    tags=('hormone therapy', 'ode', 'prostate cancer', 'androgen receptor', 'PSA'),
+    references=(BOOK, 'Jain et al. 2011'),
+    defaults={'until': 26280.0, 'dt': 168.0, 'solver': ScipyODESolver(method='LSODA')},
+)
+def prostate_androgen_receptor(
+    N: float = 1.5,
+    AD: float = 1.0,
+    AI: float = 0.0,
+    *,
+    UT: float = 40.0,
+    UD: float = 40.0,
+    m1: float = 1e-4,
+    age: float = 60.0,
+) -> System:
+    """Return the Jain model of prostate epithelium and cancer driven by activated androgen receptors, with PSA.
+
+    The growth and death rates of the normal, androgen-dependent, and androgen-independent cells follow the receptors
+    activated by testosterone, `UT`, and dihydrotestosterone, `UD`, which are parameters, so androgen ablation is a
+    lower activation. The normal cells fill a capacity that grows with the age-dependent prostate volume, and the PSA
+    the cells produce in the tissue leaks into the serum through the normal epithelium and, faster, through the
+    tumour. Cells are in billions, receptors in nM, PSA in ng/mL, and time in hours, the age in years. The book
+    leaves several parts open, filled as follows. The half saturations `psi2`, `phi2`, and `psi4` of the cancer cells
+    are those of the normal cells. The death rate is `psi3_i / (psi4 + UD + UT)`. One activation `UT`, `UD` holds
+    for all cell types, and so does `sigma`. The independent cells gain the part `m1` of the divisions of the
+    dependent cells. The negligible interaction `c1` is 0. The capacity of the normal cells is the prostate volume
+    over the volume of a billion cells, and the PSA leak rate per million cells becomes `0.3125` per billion.
+
+    Args:
+        N:
+            The initial normal epithelial cells.
+
+        AD:
+            The initial androgen-dependent cells.
+
+        AI:
+            The initial androgen-independent cells.
+
+        UT:
+            The concentration of receptors activated by testosterone.
+
+        UD:
+            The concentration of receptors activated by dihydrotestosterone.
+
+        m1:
+            The fraction of the divisions of dependent cells that yields independent cells.
+
+        age:
+            The age of the patient at the start.
+
+    Returns:
+        system:
+            The model, with the cells `prostate.N`, `prostate.AD`, and `prostate.AI`, and the PSA `prostate.UIP` in
+            the tissue and `prostate.UP` in the serum.
+
+    Examples:
+        >>> from skcomplex.models.biology.oncology import prostate_androgen_receptor
+        >>> prostate_androgen_receptor(UT=5.0).elements[0].UT
+        5.0
+    """
+    prostate = AndrogenReceptorProstateElement('prostate', N=N, AD=AD, AI=AI, UT=UT, UD=UD, m1=m1, age=age)
+    interactions = [
+        RateInteraction(
+            'normal_growth',
+            target='prostate',
+            state='N',
+            rate=lambda s: _receptor_growth(s.target, s.target.psi1_n, s.target.phi1_n)
+            * s.target.N
+            * (
+                1
+                - (s.target.N + s.target.c1 * (s.target.AD + s.target.AI))
+                / (_prostate_volume(s.target, s.t) / s.target.Vc)
+            ),
+        ),
+        ReactionInteraction(
+            'normal_death',
+            target='prostate',
+            reactants={'N': 1},
+            propensity=lambda s: _receptor_death(s.target, s.target.psi3_n) * s.target.N,
+        ),
+        RateInteraction(
+            'dependent_division',
+            target='prostate',
+            state='AD',
+            rate=lambda s: _dependent_division(s.target),
+        ),
+        ReactionInteraction(
+            'mutation',
+            target='prostate',
+            reactants={'AD': 1},
+            products={'AI': 1},
+            propensity=lambda s: s.target.m1 * _dependent_division(s.target),
+        ),
+        ReactionInteraction(
+            'dependent_death',
+            target='prostate',
+            reactants={'AD': 1},
+            propensity=lambda s: _receptor_death(s.target, s.target.psi3_d) * s.target.AD,
+        ),
+        RateInteraction(
+            'independent_growth',
+            target='prostate',
+            state='AI',
+            rate=lambda s: _receptor_growth(s.target, s.target.psi1_i, s.target.phi1_i)
+            * s.target.AI
+            * (1 - (s.target.c1 * s.target.N + s.target.AD + s.target.AI) / s.target.b3),
+        ),
+        ReactionInteraction(
+            'independent_death',
+            target='prostate',
+            reactants={'AI': 1},
+            propensity=lambda s: _receptor_death(s.target, s.target.psi3_i) * s.target.AI,
+        ),
+        RateInteraction(
+            'psa_production',
+            target='prostate',
+            state='UIP',
+            rate=lambda s: (s.target.UT + s.target.UD + s.target.sigma)
+            * (s.target.beta_n * s.target.N + s.target.beta_d * s.target.AD + s.target.beta_i * s.target.AI),
+        ),
+        ReactionInteraction(
+            'normal_leak',
+            target='prostate',
+            reactants={'UIP': 1},
+            products={'UP': 1},
+            propensity=lambda s: s.target.du1
+            * s.target.UIP
+            * s.target.N
+            / (_prostate_volume(s.target, s.t) / s.target.Vc),
+        ),
+        ReactionInteraction(
+            'cancer_leak',
+            target='prostate',
+            reactants={'UIP': 1},
+            products={'UP': 1},
+            propensity=lambda s: s.target.gamma_p
+            * s.target.UIP
+            * (s.target.AD + s.target.AI) ** 2
+            / (s.target.KP + s.target.AD + s.target.AI),
+        ),
+        ReactionInteraction(
+            'intracellular_clearance',
+            target='prostate',
+            reactants={'UIP': 1},
+            propensity=lambda s: s.target.du2 * s.target.UIP,
+        ),
+        ReactionInteraction(
+            'serum_clearance',
+            target='prostate',
+            reactants={'UP': 1},
+            propensity=lambda s: s.target.du3 * s.target.UP,
+        ),
+    ]
+    return System(elements=[prostate], interactions=interactions)
+
+
+@register_model(
+    field='biology/oncology',
+    tags=('hormone therapy', 'ode', 'prostate cancer', 'piecewise linear', 'events', 'intermittent'),
+    references=(BOOK, 'Hirata, Bruchovsky, and Aihara 2010'),
+    defaults={'until': 1500.0, 'dt': 5.0},
+)
+def piecewise_linear_ias(patient: int = 1, *, h0: float = 4.0, h1: float = 10.0) -> System:
+    """Return the Hirata piecewise-linear model of intermittent androgen suppression for one of three patient types.
+
+    The androgen-dependent, adapted, and mutated cells grow and change into each other linearly, with one set of
+    rates during therapy and one off therapy, and the therapy switches on when the PSA, the sum of the cells, rises
+    through `h1` and off when it falls through `h0`. The rates are the book's daily factors, `w = omega - 1` on the
+    diagonal and `w = omega` off it. Patient 1 does not relapse, patient 2 relapses late, and patient 3 relapses,
+    once the mutated cells outgrow the therapy. The book only states that therapy starts above 10 ng/mL, so the
+    therapy stops below 4 ng/mL and is on at the start when the PSA exceeds `h1`. The cells are in units of the PSA,
+    ng/mL, and time is in days.
+
+    Args:
+        patient:
+            The patient type, 1, 2, or 3, which sets the rates and the initial cells.
+
+        h0:
+            The PSA below which the therapy stops.
+
+        h1:
+            The PSA above which the therapy starts.
+
+    Returns:
+        system:
+            The model, with the cells `tumour.AD`, `tumour.AIR`, and `tumour.AII`, the therapy `tumour.u`, and the
+            switches as `on` and `off` events.
+
+    Raises:
+        ValidationError:
+            The patient type is not 1, 2, or 3.
+
+    Examples:
+        >>> from skcomplex.models.biology.oncology import piecewise_linear_ias
+        >>> piecewise_linear_ias(patient=3).elements[0].AD
+        11.02
+    """
+    if patient not in PATIENT_FACTORS:
+        error_msg = f'The patient type must be 1, 2, or 3, got {patient!r}.'
+        raise ValidationError(error_msg)
+    factors = PATIENT_FACTORS[patient]
+    on11, on21, on22, on31, on32, on33 = factors['on']
+    off11, off12, off22, off33 = factors['off']
+    AD, AIR, AII = factors['cells']
+    tumour = PiecewiseLinearProstateElement(
+        'tumour',
+        AD=AD,
+        AIR=AIR,
+        AII=AII,
+        u=float(h1 < AD + AIR + AII),
+        w11_on=on11 - 1,
+        w21_on=on21,
+        w22_on=on22 - 1,
+        w31_on=on31,
+        w32_on=on32,
+        w33_on=on33 - 1,
+        w11_off=off11 - 1,
+        w12_off=off12,
+        w22_off=off22 - 1,
+        w33_off=off33 - 1,
+    )
+    switches = _get_switches(
+        lambda s: s.target.x1 * s.target.AD + s.target.x2 * s.target.AIR + s.target.x3 * s.target.AII,
+        h0,
+        h1,
+    )
+    return System(elements=[tumour], interactions=switches)
+
+
+@register_model(
+    field='biology/oncology',
+    tags=('hormone therapy', 'ode', 'breast cancer', 'cell cycle', 'pharmacokinetics'),
+    references=(BOOK, 'Chen, Kirkby, and Jena 2012'),
+    defaults={'until': 2400.0, 'dt': 8.0, 'solver': ScipyODESolver(method='LSODA')},
+)
+def tamoxifen_cell_cycle(
+    Ag: float = 900.0,
+    As: float = 50.0,
+    Am: float = 50.0,
+    *,
+    u: float = 12.5,
+    a1: float = 0.0062,
+    a2: float = 0.010,
+) -> System:
+    """Return a breast tumour in Gompertzian cell-cycle phases under daily tamoxifen and its active metabolite.
+
+    The cells pass from the growth phase through synthesis to mitosis and divide back into the growth phase, at
+    rates that slow as the tumour approaches `Asat`. Tamoxifen is absorbed from the gut into the plasma, where it is
+    metabolized into 4-hydroxytamoxifen, and both kill cells in the growth phase, the metabolite 25 times more. They
+    also kill circulating lymphocytes, which stay at `s / d1` without the drug. The book gives no infusion rate, so the
+    default `u` is 300 μg a day, given continuously. Volumes are in mm³, drug masses in μg, concentrations in
+    μg/mL, lymphocytes in millions, and time in hours.
+
+    Args:
+        Ag:
+            The initial volume of cells in the growth phase.
+
+        As:
+            The initial volume of cells in the synthesis phase.
+
+        Am:
+            The initial volume of cells in mitosis.
+
+        u:
+            The infusion rate of tamoxifen.
+
+        a1:
+            The kill rate of the tumour per unit of drug.
+
+        a2:
+            The kill rate of the lymphocytes per unit of drug.
+
+    Returns:
+        system:
+            The model, with the phases `tumour.Ag`, `tumour.As`, and `tumour.Am`, the drug masses `tumour.X0` to
+            `tumour.X3`, and the lymphocytes `tumour.E`.
+
+    Examples:
+        >>> from skcomplex.models.biology.oncology import tamoxifen_cell_cycle
+        >>> tamoxifen_cell_cycle(u=0.0).elements[0].u
+        0.0
+    """
+    tumour = TamoxifenTumourElement('tumour', Ag=Ag, As=As, Am=Am, u=u, a1=a1, a2=a2)
+    interactions = [
+        ReactionInteraction(
+            'g1_exit',
+            target='tumour',
+            reactants={'Ag': 1},
+            products={'As': 1},
+            propensity=lambda s: s.target.mg * s.target.Ag * _room(s.target),
+        ),
+        ReactionInteraction(
+            'synthesis',
+            target='tumour',
+            reactants={'As': 1},
+            products={'Am': 1},
+            propensity=lambda s: s.target.ms * s.target.As,
+        ),
+        ReactionInteraction(
+            'mitosis',
+            target='tumour',
+            reactants={'Am': 1},
+            products={'Ag': 2},
+            propensity=lambda s: s.target.mm * s.target.Am * _room(s.target),
+        ),
+        ReactionInteraction(
+            'drug_kill',
+            target='tumour',
+            reactants={'Ag': 1},
+            propensity=lambda s: s.target.a1
+            * s.target.Ag
+            * (s.target.X2 / s.target.V + s.target.delta1 * s.target.X3 / s.target.V),
+        ),
+        DosingInteraction('dosing', target='tumour', state='X0', dose=lambda s: s.target.u),
+        ReactionInteraction(
+            'absorption',
+            target='tumour',
+            reactants={'X0': 1},
+            products={'X1': 1},
+            propensity=lambda s: s.target.k01 * s.target.X0,
+        ),
+        ReactionInteraction(
+            'transport',
+            target='tumour',
+            reactants={'X1': 1},
+            products={'X2': 1},
+            propensity=lambda s: s.target.k12 * s.target.X1,
+        ),
+        ReactionInteraction(
+            'metabolism',
+            target='tumour',
+            reactants={'X2': 1},
+            products={'X3': 1},
+            propensity=lambda s: s.target.k23 * s.target.X2,
+        ),
+        ReactionInteraction(
+            'tamoxifen_clearance',
+            target='tumour',
+            reactants={'X2': 1},
+            propensity=lambda s: s.target.du1 * s.target.X2,
+        ),
+        ReactionInteraction(
+            'metabolite_clearance',
+            target='tumour',
+            reactants={'X3': 1},
+            propensity=lambda s: s.target.du2 * s.target.X3,
+        ),
+        RateInteraction('effector_source', target='tumour', state='E', rate=lambda s: s.target.s),
+        ReactionInteraction(
+            'effector_death',
+            target='tumour',
+            reactants={'E': 1},
+            propensity=lambda s: s.target.d1 * s.target.E,
+        ),
+        ReactionInteraction(
+            'effector_drug_kill',
+            target='tumour',
+            reactants={'E': 1},
+            propensity=lambda s: s.target.a2
+            * s.target.E
+            * (s.target.X2 / s.target.V + s.target.delta2 * s.target.X3 / s.target.V),
+        ),
+    ]
+    return System(elements=[tumour], interactions=interactions)