def adjust_pool_bounds(self,
min_objective=0.05,
inplace=False,
tolerance=1e-9):
"""Adjust protein pool bounds minimally to make model feasible.
Bounds from measurements can make the model non-viable or even infeasible. Adjust these minimally by minimizing
the positive deviation from the measured values.
:param min_objective: float, The minimum value of for the ojective for calling the model viable.
:param inplace: bool, Apply the adjustments to the model.
:param tolerance: float, Minimum non-zero value. Solver specific value.
:returns: pd.DataFrame, Data frame with the series 'original' bounds and the new 'adjusted' bound, \
and the optimized 'addition'.
"""
from reframed.solvers import solver_instance
solver = solver_instance(self)
solver.add_constraint('constraint_objective',
self.get_objective,
sense='>',
rhs=min_objective)
for pool in self.individual_protein_exchanges:
solver.add_variable('pool_diff_' + pool.id, lb=0)
solver.add_variable('measured_bound_' + pool.id,
lb=pool.upper_bound,
ub=pool.upper_bound)
def build_ensemble(model, reaction_scores, size, init_env=None):
""" Reconstruct a model ensemble using the CarveMe approach.
Args:
model (CBModel): universal model
reaction_scores (dict): reaction scores
size (int): ensemble size
outputfile (str): write model to SBML file (optional)
flavor (str): SBML flavor ('cobra' or 'fbc2', optional)
init_env (Environment): initialize final model with given Environment (optional)
Returns:
EnsembleModel: reconstructed ensemble
"""
scores = dict(reaction_scores[['reaction', 'normalized_score']].values)
unscored = [
r_id for r_id in model.reactions
if r_id not in scores and not r_id.startswith('R_EX')
]
logstd = np.std(np.log([x for x in scores.values() if x > 0]))
reaction_status = {r_id: [] for r_id in model.reactions}
solver = solver_instance(model)
failed = 0
for i in range(size):
random_scores = -np.exp(logstd * np.random.randn(len(unscored)))
all_scores = dict(zip(unscored, random_scores))
all_scores.update(scores)
sol = minmax_reduction(model, all_scores, solver=solver)
if sol.status == Status.OPTIMAL:
for r_id in model.reactions:
active = (abs(sol.values[r_id]) >= 1e-6
or (sol.values.get('yf_' + r_id, 0) > 0.5)
or (sol.values.get('yr_' + r_id, 0) > 0.5))
reaction_status[r_id].append(active)
else:
failed += 1
ensemble_size = size - failed
ensemble = EnsembleModel(model, ensemble_size, reaction_status)
ensemble.simplify()
for i, row in reaction_scores.iterrows():
r_id = row['reaction']
if r_id in ensemble.model.reactions:
gpr = parse_gpr_rule(row['GPR'])
ensemble.model.reactions[r_id].set_gpr_association(gpr)
if init_env:
init_env.apply(ensemble.model, inplace=True, warning=False)
def gapFill(model,
universe,
constraints=None,
min_growth=0.1,
scores=None,
inplace=True,
bigM=1e3,
abstol=1e-9,
solver=None,
tag=None):
""" Gap Fill a metabolic model by adding reactions from a reaction universe
Args:
model (CBModel): original model
universe (CBModel): universe model
constraints (dict): additional constraints (optional)
min_growth (float): minimum growth rate (default: 0.1)
scores (dict): reaction scores (optional, see notes)
inplace (bool): modify given model in place (default: True)
bigM (float): maximal reaction flux (default: 1000)
abstol (float): minimum threshold to consider a reaction active (default: 1e-9)
solver (Solver): solver instance (optional)
tag (str): add a metadata tag to gapfilled reactions (optional)
Returns:
CBModel: gap filled model (if inplace=False)
Notes:
Scores can be used to make some reactions more likely to be included.
Scored reactions have a penalty of 1/(1+score), which varies between [0, 1].
Unscored reactions have a penalty of 1.
"""
new_reactions = set(universe.reactions) - set(model.reactions)
model = merge_models(model, universe, inplace, tag=tag)
for r_id in new_reactions:
if r_id.startswith('R_EX'):
model.set_flux_bounds(r_id, lb=0)
if not solver:
solver = solver_instance(model)
if not scores:
scores = {}
if not hasattr(solver, '_gapfill_flag'):
solver._gapfill_flag = True
for r_id in new_reactions:
solver.add_variable('y_' + r_id,
0,
1,
vartype=VarType.BINARY,
update=False)
solver.update()
for r_id in new_reactions:
solver.add_constraint('lb_' + r_id, {
r_id: 1,
'y_' + r_id: bigM
},
'>',
0,
update=False)
solver.add_constraint('ub_' + r_id, {
r_id: 1,
'y_' + r_id: -bigM
},
'<',
0,
update=False)
biomass = model.biomass_reaction
solver.add_constraint('min_growth', {biomass: 1},
'>',
min_growth,
update=False)
solver.update()
objective = {
'y_' + r_id: 1.0 / (1.0 + scores.get(r_id, 0.0))
for r_id in new_reactions
}
solution = solver.solve(linear=objective,
minimize=True,
constraints=constraints)
if solution.status == Status.OPTIMAL:
inactive = [
r_id for r_id in new_reactions
if abs(solution.values[r_id]) < abstol
]
else:
raise RuntimeError('Failed to gapfill model for medium {}'.format(tag))
model.remove_reactions(inactive)
del_metabolites = disconnected_metabolites(model)
model.remove_metabolites(del_metabolites)
if not inplace:
return model
def multiGapFill(model,
universe,
media,
media_db,
min_growth=0.1,
max_uptake=10,
scores=None,
inplace=True,
bigM=1e3,
spent_model=None):
""" Gap Fill a metabolic model for multiple environmental conditions
Args:
model (CBModel): original model
universe (CBModel): universe model
media (list): list of growth media ids
media_db (dict): growth media database (see notes)
min_growth (float): minimum growth rate (default: 0.1)
max_uptake (float): maximum uptake rate (default: 10)
scores (dict): reaction scores (optional, see *gapFill* for details)
inplace (bool): modify given model in place (default: True)
bigM (float): maximal reaction flux (default: 1000)
spent_model (CBModel): additional species to generate spent medium compounds
Returns:
CBModel: gap filled model (if inplace=False)
Notes:
*media_db* is a dict from medium name to the list of respective compounds.
"""
ABSTOL = 1e-6
if not inplace:
model = model.copy()
new_reactions = set(universe.reactions) - set(model.reactions)
for r_id in new_reactions:
if r_id.startswith('R_EX'):
universe.set_flux_bounds(r_id, lb=0)
merged_model = merge_models(model, universe, inplace=False)
solver = solver_instance(merged_model)
if spent_model:
solver0 = solver_instance(spent_model)
for medium_name in media:
if medium_name in media_db:
compounds = set(media_db[medium_name])
constraints = medium_to_constraints(merged_model,
compounds,
max_uptake=max_uptake,
inplace=False,
verbose=False)
if spent_model:
constraints0 = medium_to_constraints(spent_model,
compounds,
max_uptake=max_uptake,
inplace=False,
verbose=False)
for r_id in spent_model.get_exchange_reactions():
if r_id in constraints:
sol = FBA(spent_model,
objective={r_id: 1},
constraints=constraints0,
solver=solver0,
get_values=False)
if sol.fobj > ABSTOL:
constraints[r_id] = (-max_uptake, None)
print("added", r_id[5:-2], "to", medium_name)
gapFill(model,
universe,
constraints=constraints,
min_growth=min_growth,
scores=scores,
inplace=True,
bigM=bigM,
solver=solver,
tag=medium_name)
else:
print('Medium {} not in database, ignored.'.format(medium_name))
return model
def simulate(self,
objective=None,
method=SimulationMethod.FBA,
maximize=True,
constraints=None,
reference=None,
scalefactor=None,
solver=None):
'''
Simulates a phenotype when applying a set constraints using the specified method.
:param dic objective: The simulation objective. If none, the model objective is considered.
:param method: The SimulationMethod (FBA, pFBA, lMOMA, etc ...)
:param boolean maximize: The optimization direction
:param dic constraints: A dictionary of constraints to be applied to the model.
:param dic reference: A dictionary of reaction flux values.
:param float scalefactor: A positive scaling factor for the solver. Default None.
:param solver: An instance of the solver.
'''
if not objective:
objective = self.model.get_objective()
simul_constraints = OrderedDict()
if constraints:
simul_constraints.update(constraints)
if self.constraints:
simul_constraints.update(self.constraints)
if self.environmental_conditions:
simul_constraints.update(self.environmental_conditions)
a_solver = solver
if not self._reset_solver and not a_solver:
if self.solver is None:
self.solver = solver_instance(self.model)
a_solver = self.solver
# scales the model if a scalling factor is defined.
# ... scalling should be implemented at the solver level.
if scalefactor:
for _, rxn in self.model.reactions.items():
rxn.lb = rxn.lb * scalefactor
rxn.ub = rxn.ub * scalefactor
if simul_constraints:
for idx, constraint in simul_constraints.items():
if isinstance(constraint, (int, float)):
simul_constraints[idx] = constraint * scalefactor
elif isinstance(constraint, tuple):
simul_constraints[idx] = tuple(x * scalefactor
for x in constraint)
else:
raise ValueError("Could not scale the model")
# TODO: simplifly ...
if method in [
SimulationMethod.lMOMA, SimulationMethod.MOMA,
SimulationMethod.ROOM
] and reference is None:
reference = self.reference
if method == SimulationMethod.FBA:
solution = FBA(self.model,
objective=objective,
minimize=not maximize,
constraints=simul_constraints,
solver=a_solver)
elif method == SimulationMethod.pFBA:
solution = pFBA(self.model,
objective=objective,
minimize=not maximize,
constraints=simul_constraints,
solver=a_solver,
obj_frac=0.999)
elif method == SimulationMethod.lMOMA:
solution = lMOMA(self.model,
constraints=simul_constraints,
reference=reference,
solver=a_solver)
elif method == SimulationMethod.MOMA:
solution = MOMA(self.model,
constraints=simul_constraints,
reference=reference,
solver=a_solver)
elif method == SimulationMethod.ROOM:
solution = ROOM(self.model,
constraints=simul_constraints,
reference=reference,
solver=a_solver)
# Special case in which only the simulation context is required without any simulatin result
elif method == SimulationMethod.NONE:
solution = Solution(status=s_status.UNKNOWN,
message=None,
fobj=None,
values=None)
else:
raise Exception("Unknown method to perform the simulation.")
# undoes the model scaling
if scalefactor:
for _, rxn in self.model.reactions.items():
rxn.lb = rxn.lb / scalefactor
rxn.ub = rxn.ub / scalefactor
if solution.status in (s_status.OPTIMAL, s_status.SUBOPTIMAL):
solution.fobj = solution.fobj / scalefactor
for x, y in solution.values.items():
solution.values[x] = y / scalefactor
status = self.__status_mapping[solution.status]
result = SimulationResult(self.model,
solution.fobj,
fluxes=solution.values,
status=status,
envcond=self.environmental_conditions,
model_constraints=self.constraints,
simul_constraints=constraints,
maximize=maximize)
return result
def minmax_reduction(model,
scores,
min_growth=0.1,
min_atpm=0.1,
eps=1e-3,
bigM=1e3,
default_score=-1.0,
uptake_score=0.0,
soft_score=1.0,
soft_constraints=None,
hard_constraints=None,
ref_reactions=None,
ref_score=0.0,
solver=None,
debug_output=None):
""" Apply minmax reduction algorithm (MILP).
Computes a binary reaction vector that optimizes the agreement with reaction scores (maximizes positive scores,
and minimizes negative scores). It generates a fully connected reaction network (i.e. all reactions must be able
to carry some flux).
Args:
model (CBModel): universal model
scores (dict): reaction scores
min_growth (float): minimal growth constraint
min_atpm (float): minimal maintenance ATP constraint
eps (float): minimal flux required to consider leaving the reaction in the model
bigM (float): maximal reaction flux
default_score (float): penalty score for reactions without an annotation score (default: -1.0).
uptake_score (float): penalty score for using uptake reactions (default: 0.0).
soft_score (float): score for soft constraints (default: 1.0)
soft_constraints (dict): dictionary from reaction id to expected flux direction (-1, 1, 0)
hard_constraints (dict): dictionary of flux bounds
solver (Solver): solver instance (optional)
Returns:
Solution: optimization result
"""
if not solver:
solver = solver_instance(model)
objective = {}
scores = scores.copy()
reactions = list(scores.keys())
if soft_constraints:
reactions += [
r_id for r_id in soft_constraints if r_id not in reactions
]
else:
soft_constraints = {}
if not ref_reactions:
ref_reactions = {}
if hard_constraints:
solver.set_bounds(hard_constraints)
if default_score != 0:
for r_id in model.reactions:
if r_id not in reactions and r_id not in ref_reactions and not r_id.startswith(
'R_EX') and r_id != 'R_ATPM':
scores[r_id] = default_score
reactions.append(r_id)
if ref_score != 0:
for r_id in ref_reactions:
if r_id not in reactions and r_id != 'R_ATPM':
scores[r_id] = ref_score
reactions.append(r_id)
if not hasattr(solver, '_carveme_flag'):
solver._carveme_flag = True
biomass = model.biomass_reaction
solver.add_constraint('min_growth', {biomass: 1},
'>',
min_growth,
update=False)
solver.add_constraint('min_atpm', {'R_ATPM': 1},
'>',
min_atpm,
update=False)
solver.neg_vars = []
solver.pos_vars = []
for r_id in reactions:
if model.reactions[r_id].lb is None or model.reactions[r_id].lb < 0:
y_r = 'yr_' + r_id
solver.add_variable(y_r,
0,
1,
vartype=VarType.BINARY,
update=False)
solver.neg_vars.append(y_r)
if model.reactions[r_id].ub is None or model.reactions[r_id].ub > 0:
y_f = 'yf_' + r_id
solver.add_variable(y_f,
0,
1,
vartype=VarType.BINARY,
update=False)
solver.pos_vars.append(y_f)
if uptake_score != 0:
for r_id in model.reactions:
if r_id.startswith('R_EX'):
solver.add_variable('y_' + r_id,
0,
1,
vartype=VarType.BINARY,
update=False)
solver.update()
for r_id in reactions:
y_r, y_f = 'yr_' + r_id, 'yf_' + r_id
if y_r in solver.neg_vars and y_f in solver.pos_vars:
solver.add_constraint('lb_' + r_id, {
r_id: 1,
y_f: -eps,
y_r: bigM
},
'>',
0,
update=False)
solver.add_constraint('ub_' + r_id, {
r_id: 1,
y_f: -bigM,
y_r: eps
},
'<',
0,
update=False)
solver.add_constraint('rev_' + r_id, {
y_f: 1,
y_r: 1
},
'<',
1,
update=False)
elif y_f in solver.pos_vars:
solver.add_constraint('lb_' + r_id, {
r_id: 1,
y_f: -eps
},
'>',
0,
update=False)
solver.add_constraint('ub_' + r_id, {
r_id: 1,
y_f: -bigM
},
'<',
0,
update=False)
elif y_r in solver.neg_vars:
solver.add_constraint('lb_' + r_id, {
r_id: 1,
y_r: bigM
},
'>',
0,
update=False)
solver.add_constraint('ub_' + r_id, {
r_id: 1,
y_r: eps
},
'<',
0,
update=False)
if uptake_score != 0:
for r_id in model.reactions:
if r_id.startswith('R_EX'):
solver.add_constraint('lb_' + r_id, {
r_id: 1,
'y_' + r_id: bigM
},
'>',
0,
update=False)
solver.update()
for r_id in reactions:
y_r, y_f = 'yr_' + r_id, 'yf_' + r_id
if r_id in soft_constraints:
sign = soft_constraints[r_id]
if sign > 0:
w_f, w_r = soft_score, 0
elif sign < 0:
w_f, w_r = 0, soft_score
else:
w_f, w_r = -soft_score, -soft_score
if y_f in solver.pos_vars:
if r_id in soft_constraints:
objective[y_f] = w_f
elif r_id in ref_reactions:
objective[y_f] = 2 * scores[r_id] + ref_score
else:
objective[y_f] = scores[r_id]
if y_r in solver.neg_vars:
if r_id in soft_constraints:
objective[y_r] = w_r
elif r_id in ref_reactions:
objective[y_r] = 2 * scores[r_id] + ref_score
else:
objective[y_r] = scores[r_id]
if uptake_score != 0:
for r_id in model.reactions:
if r_id.startswith('R_EX') and r_id not in soft_constraints:
objective['y_' + r_id] = uptake_score
solver.set_objective(linear=objective, minimize=False)
if debug_output:
solver.write_to_file(debug_output + "_milp_problem.lp")
solution = solver.solve()
return solution