Computational Methods in Systems Biology

Detecting Toxicity Pathways with a Formal Framework 201

Consequently, our domain-oriented formalism represent the evolution of the
concentration of each entity as a change in its equilibrium level. In that line, we
introduce four qualitative equilibrium levels depicting increasing concentrations
of an entity:

• εstands for a negligible concentration (i.e.a concentration too low to trigger
  any reaction in the biological system).


• ιstands for an abnormally low concentration (i.e.a relative lack of this entity,
  affecting some mechanisms in the biological system).


• Δstands for a normal concentration.


• θstands for an abnormally high concentration (i.e.an excess of this entity).

Notation 1(Concentration levels).We noteLthe set{ε, ι, Δ, θ}equipped
with the total order relation such that:ε<ι<Δ<θ. The elements ofLare
calledconcentration levels.

In a given biological system and depending on the studied issue, not all levels
are regarded as useful. For example, the modeler may be only interested in the
normal (Δ) or excessive (θ) presence of an entity. Therefore, an entity must have
at least two levels, but not necessarily more. The signature of a biological system
allows the definition of the set of biological entities considered in the system and,
for each entity, its admissible concentration levels.

Definition 1(Signature).Asignatureis a mapE:E→P(L)where E is a
finite set and for alle∈E,|E(e)| 2. Elements of E are calledentitiesand for
each entitye,E(e)is the set ofadmissible levelsofe.

For instance,E={T 3 ,T 4 ,TPO,I}can be the signature of a thyroid model,
withE(T 3 )={ε, ι, Δ, θ},E(T 4 )={ε, ι, Δ, θ},E(TPO) ={ε, ι, Δ, θ}andE(I) =
{ε, Δ, θ}.
After defining the system signature, a state of the system is defined as the
qualitative level of each entity present in the system. For example, a stateη 0
where T 3 is at the levelΔ, notedη 0 (T 3 )=Δand whereη 0 (T 4 )=ε,η 0 (TPO) =ι
andη 0 (I) =θ. This state can also be written:

η 0 =(Δ, ε, ι, θ) (1)

where the entities order is (T 3 ,T 4 ,TPO,I).

Definition 2(State).A signatureEbeing given, the set of statesζis the set
of functionsη :E→Lsuch that for alle∈E,η(e)∈E(e).

In our formalism, the evolution of an entity can follow two functions: the
incrementation,incr, and the decrementation,decr. They return the level of
this entity just above (resp. below) its current level. For instance, asE(TPO) =
{ε, Δ, θ},incrTPO(Δ)=θanddecrTPO(Δ)=ε. Note that the incrementation
(resp. decrementation) function is not defined on the maximal (resp. minimal)
admissible levels. As such,incrTPO(η(TPO)) is not defined ifη(TPO) =θ.
Besides these functions, the formalism also makes use of formulas to describe
properties about the entities concentration levels.