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 Complex Systems and Their Use in Medicine:
Concepts, Methods and
Bio-Medical Applications

Jiri Kroca*, Ph.D. Karel Baliharb, MD, and Martin Matějoviča,b MD.
a
Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
b
1st Medical Department, Teaching Hospital, Faculty of Medicine in Pilsen, Charles
University, Pilsen, Czech Republic

ABSTRACT
This review aims mainly to all professionals from the fields of clinical
medicine, biomedical and experimental research. It targets to deliver a quick
starting overview and basic understanding of Complex Systems (CSs) with a
citation apparatus enabling to efficiently reach the cutting-edge knowledge and
applications. This paper has two main objectives. It builds the core
information of CSs that is explained on a carefully selected example called the
“Game of Life”, which expresses self-organization and emergence. The
second and most important objective is to provide a wide list of CSs
computational methods enabling everybody to achieve a basic overview of all
major methods applied in experimental and clinical medicine. These methods
are easy to implement in any field of the interest.

KEY WORDS: complex systems; models; predictive medicine; personalized

medicine; self-organization; emergence;

INTRODUCTION
A fast development of modern mathematical methods occurring within the
field of complex systems (CSs) enables clinical and experimental medicine to
quantify and subsequently study many so far unavailable information key of
the functioning of biological structures. The fast development of CSs is
inseparably based on the accelerated development of modern computers and
computational techniques; undoubtedly, they can support the exploration of
wetware applications1,2. Wetware is biological ‘hardware’ in which
computational principles are often implemented in unexpected ways.
According to a modern view of CSs achieved relatively recently, a living
entity can be from a certain simplified point of view observed as a multilevel
computational device1,3,4. We are aware of the fact that biomedical research is
fragmented into disciplines and sub-disciplines without sufficient use of
unifying approaches where the majority of methods are often focused only to
*Corresponding e-mail: dr.j.kroc@gmail.com
1
study selected, particular process(es) unrelated or indirectly related to the
whole. CSs provide the opposite direction: they build the whole from its parts.
Until relatively recently, biologists and physicians were not aware of the
presence of emergent levels where bio-computations operate. Therefore, the
contemporary cutting-edge bio-medical praxis and research requires a close
cooperation between mathematicians, medical doctors from clinics and the
research field because they are not usually fully informed about the latest
development of the respective field. The extraordinary ability of complex
systems to study synthesis is opposing to the overused reductionism and
’dissection’. The basic processes operating within CSs, self-organization and
emergence, provide a set of unique tools that are capable to describe any
biological system as a whole.
Our mathematical thinking is often distorted by the methods we are taught
and that we commonly use without even noticing it. This review is designed in
the way to help non-mathematicians realize it and subsequently to overcome it
by providing a concise overview of computational methods developed within
CSs that are applied in medicine and biology. First, the minimal core of the
knowledge is built on one, carefully selected, prototypic example of ”the
Game of Life”3, and subsequently, a practical overview of the most important
methods used in CSs is demonstrated (Table 1). This is followed by the
overview of all major computational methods in biomedicine. Additionally,
the review provides information necessary to bridge the information gap
between medicine on one hand, and mathematical and computational methods
developed in complex systems on the other hand.

WHAT ARE COMPLEX SYSTEMS?

There is an apparent development of mathematical methods applied within
science, which is going from analytical ones which can be performed without
use of computers), towards those more complex (requiring use of computers).
The development of methods is closely correlated to the development of
computational tools. Originally, only manual computations were possible,
which started to develop fast in the 17th century. Hence, analytical and simple
statistical mathematical methods were the only choice. The invention of
computers enabled the development of computational methods. First,
discretized models [e.g. finite element method (FEM)] typically derived from
a set of differential equations [e.g. partial differential equations (PDE)] were
evaluated5-7. Discretized, numerical models enabled to solve even equations
where analytical solutions are unknown8. This led to the acceleration of
description of many phenomena observed within the Nature. Later, new types
of models better tailored to computers were developed, e.g. Monte Carlo
method9,10, dynamical systems and chaos11. Complex systems4,12-14 represent
the latest stage of this mathematical development; they are based on a set of

2
brand new ideas compared to older analytical models (Table 2). CSs heavily
rely on the use of powerful computers and computer simulations (Footnote1).

Table 1 List of the major computational methods developed within complex systems that are used in
medicine and biology: methods principles and examples of their use shown (the order do not represent
the importance of the method). More rigorous definitions of methods follow in Table 3.

Method Name and Principle Examples of the method use in medicine

Agent Based Models (ABMs): Autonomous Cell-cell interactions78, cancer38,40, tissues28,

agents represent entities, which mutually interact microbial interactions49, immune systems47,48;
according to physically relevant rules (forces). social interactions [escape behavior, pools, votes,
etc.](ref. 18,19); military combat13.

Cellular Automata (CAs): The space is divided Cell-cell interactions, cancer37,40, and tissue
into a lattice where each lattice element interacts modelling78, social interactions, spread of
with its neighbors according to a predefined, diseases4, heart and retinal excitations.
governing-rule; simulation proceeds in discrete
time steps.

Theory of Games (ToGs): Agents positioned Social interaction, economical systems, microbial
on/off a lattice play games locally (pairs, interactions, cellular ensembles are modelled by
multiple). The outcomes of agent’s interactions ToGs. Evolutionary games are a natural extension
drive the global evolution of the system. of ToGs42,43.

Lattice Boltzmann Method (LBM): Method
based on evaluation of fictive particles flow
defined by Boltzmann equation36. It is based on
physically relevant quantities (is more advanced
than Navier-Stokes equations [NSE]).
Fluid flow (blood) in aneurysm29, veins, aorta,
heart valves, tissue remodeling79, tissue perfusion,
blood flow30. Averages of quantities evaluated by
LBM provide the same values as NSE.

Lattice Gas Method (LGM): Evaluate fluid flow Flow of liquids and gasses (blood flow,
where fictive particles are moving in the six respiration); more advanced than NSE. Averages
predefined directions and mutually collides give NSE.
(derived from CAs; the predecessor of LBM).

Complex Networks (CXNs): Nodes and links Gene regulatory networks (GRN), disease-gene
represent parts and mutual interactions of the dependences in population, networked
system, respectively; they create a network (e.g. medicine54,60,62; ecosystems, brain functioning.
small-world, scale-free, random), its shape greatly Measuring of entropy45.
influences system’s dynamics44.

Networked Biology (NB): NB means
understanding of the cell’s functional organization,
which is operating at many scales and through
various media (DNA, proteins, signaling
molecules …) simultaneously. NB is described
using CXNs.
Links among cell’s components define networks
that are studied, e.g., proteins, signaling cascades,
regulatory networks, etc. The network of all
networks is called the interactome54,59,30,62.

Networked Medicine (NM): NM explores Diseasome (the network of phenotypes-diseased

possibilities of network-based approach to human genes)60,62, interactome (cell’s components
disease. It will ultimately comprise all levels of influenced by other components)(ref. 54) .
emergents54,60,62.

1 Computer simulations can be roughly divided into the following categories: (i) deterministic
(predecessor(s) precisely define any successor), (ii) stochastic (successor is randomly defined with some
weak dependence to predecessor(s)), (iii) continuous (variables are continuous), (iv) discrete (variables
are discrete), (v) local (everything is computed on a single processor), (vi) distributed (multiple
processors or computers are used in computation), (vii) sequential (information processed step-by-step),
and (viii) massively parallel (all information processed totally in parallel).
3
Complex Systems Measures (CSMs): CSMs are
based on the notion of entropy (e.g., information
entropy, and other types of entropies). They
measure order/disorder of systems and hence their
information content.
Deal with the signal classification: ECGs 22,23,
EEGs24,25, gait studies26, apnea27, and all other
measurable biological data. It is going from the
level of supra-atomic level to the level of the
whole-bodies.

Machine Learning (ML): ML is based on an idea
of an automated search for generalized
dependencies among data; extracts data
dependencies inaccessible by standard methods
(analytical, statistical, etc.) using specialized
algorithms. Replace curves and equations by
concepts that are more abstract65,66,80,81.
It is represented by methods: regression (linear &
nonlinear), neuronal networks, Gaussian learning,
decision trees, k-nearest neighbors, k-means,
random forest, logistic regression, support vector
machine, etc. Many learning techniques that are
not explicitly programmed fail in this class65,66,80,81.

Data Mining (DM): DM extracts information
from large data sets in an understandable form. It
uses methods from machine learning, artificial
intelligence, statistics, and database systems.
Search for more abstract dependencies 81,82 than
ML and goes beyond it. Huge data stored in
databases are searched by many methods to find
any viable information. DM pinpoints certain
features among data along with their dependencies
and often shows research paths to use of other
methods during their own search.

Multi-Scale Models (MSMs): MSMs capture
processes, which are occurring at multiple scales
in time and space. They are composed from
different, mutually communicating models
operating on different scales80,83-85.
In biology, MSMs of fluids, solids, polymers,
proteins86, nucleic acids, and immune system
exist47,48. Existing models of physical and chemical
phenomena are adsorption, chemical reactions,
and diffusion.

Currently, there does not exist any general theory of CSs. The most often
used definition of a CS reads “CS is as an ensemble of a vast number of copies
of several generic entities (processes) operating simultaneously, which are
mutually communicating. An entity typically interacts with a restricted number
of its neighbors (including itself), not necessary close ones, and adjusts its
future behavior according to them”14.

Figure 1: Two sub-sequent steps of the CA called the “Game of Life” are depicted where
small, emergent structures having size of 5-cells (called gliders) operate. Gliders are produced
by the oscillating structure (called glider-gun), are traveling through the space (southeast), and
they are maintaining their integrity endlessly until they eventually meet another structure.
Simulation runs on a rectangular lattice of cells where the smallest visible square represents
one computational cell.

4
 Cellular Automata (CAs) represent a special case of CSs where a space is
discretized into a uniform lattice of elements (e.g. squares, triangles, or
hexagons in two dimensions or cubes in three dimensions) called cells and
where time proceeds in discrete time steps12,14. Generally, the values of all
variables attached to each process (cell) are changed to their new values
according to a uniform governing (also transition, evolution, CAs) rule
simultaneously for each new time step. The governing-rule is identical for
each process and handles the evolution of the system. The information flow is
centripetal. There are several ways to build a clear and concise explanation of
the key ideas hidden within the core of CSs. One of the most useful ways is
considered to be a CA called the “Game of Life”, which is very clear and
proven by many years of use3. GoL is capable to elucidate self-organizing and
emergent behavior using a tiny CA-rule (drives evolution of the CA) that can
be written just within three lines of code (Figure 1). The code can run on a
CA-parallel computer or a software emulator of it (animations can be found at
Wikipedia - ”Conway's_Game_of_Life”). While observing a simulation of the
glider gun and gliders (Figure 1) everybody can realize that medicine can be
much simpler than we expect but currently we do not know how to achieve it.
We simply do not know in which directions to look for explanations of
biologically observed phenomena.

Table 2 A list of the major mathematical methods and their respective techniques.

Mathematical How Are They Built?

Disciplines: Generic
Methods

Arithmetic Numbers represents counts of entities. The same ’numbers’/symbols are used
for different entities (e.g. sheep, stones, and people). Arithmetic studies
numbers and four related, simple operations: addition, subtraction,
multiplication, and division.

Algebra Symbols used instead of numbers. Simple relationships are expressed in

equations using those symbols. Generally, operations with symbols are
studied.

Equations [e.g., partial Numbers are replaced by functions where function can be understood as a
(PDEs) and ordinary large sequence of numbers, where more complicated relationships among
(ODEs) differential variables are expressed. Differential equations relate functions with their
equations] derivatives. They are usually derived using the mean-filed approximation,
renormalization, or some other sort of averages of local values 5-7.

Statistics & probability Statistics study large numbers of observations and ensembles that are used to
make predictions: averages, deviations, distributions. Probability defines the
likelihood that given events will occur70.

Mathematical Models Models describe systems using mathematical methods and tools. They
approximate the real system using some sort of abstraction 71.

Computer Simulations Computer simulations are programs that run mathematical models in a
computer. Simulations can be split into the following categories (they can
simultaneously belong into more than one): deterministic, stochastic,
dynamic systems, continuous, discrete, local, distributed, sequential, and
massively parallel9.

5
Nonlinear Dynamical A dynamical system is a system where its variables evolve according to some
Systems & Chaos fixed prescription within a state space. Examples are Lorenz system, logistic
map, double pendulum, Hénon map, etc. A chaotic behavior, called
deterministic chaos is observed in fully deterministic systems (e.g., logistic
curve)(ref.11,72,73).

Fractals Fractals are sets exhibiting a repeating pattern on each scale. If the same
pattern is applied on the infinite number of scales then it is called a self-
similar one74,75.

Complex Systems Systems composed of a large number of locally interacting entities

(processes) that are relatively simple, which produce self-organization and
emergent behavior14,76,77.

The governing-rule of GoL is based on the sum of values stored at all eight
neighbors located at positions relative to the cell under consideration and it is
therefore called the totalistic rule. The values of variables from cells located at
the old time layer defines what happen with variables in the new time layer.
When just three neighboring cells are alive, the cell stays or becomes alive.
When two neighboring cells and the cell under consideration are alive, the cell
under consideration stays alive. Otherwise, the cell under consideration stays
or becomes dead, see details15. Time proceeds in discrete steps. The similarity
between this artificial ‘game’ and behavior of real living structure is
astonishing3 (Figure 2, 3).

Figure 2: Two instances of gliders are depicted where the upper parts depict the previous time
step at time (t-1) and the lower parts depict the next step at time (t). Little squares at time (t-1)
represent places where the centers of the alive cells will be located in the next time step (t).
Little squares are expanded to full squares at the lower part of the picture at time (t). In the
next time step, gliders at the lower part of the picture at the time step (t) become old ones and
new gliders are similarly created at the time step (t+1). This procedure goes on infinitely until
the gliders collide.

6
Figure 3: A hierarchy of emergents observed within human bodies where each emergent level
express an unique type of emergents having their own, unique interaction rules. Cross-scale
interactions among emergents of different kind are for simplicity not depicted in this figure
but in real living systems are operating (e.g. hormones, blood pressure).

7
Self-organization and emergence
Self-organization is a process that inevitably leads a CS system (composed
of mutually interacting parts) into a global state, which is not encoded within
behavior of its constituting parts; that all irrespectively of the initial
conditions. Think of dichotomies ants–ant colony16, people–opinion creation,
people voting, crowd wisdom17 and people–escape behavior18,19, car traffic
flow20, bacteria–bacterial colonies21, and skin cells-fur patterns. Self-
organization can lead to production of novel entities called emergents, which
are operating at a higher organizational-level. Higher-level entities are
behaving according to different interaction governing-rules than are those
present at the lower level of the systems. For example, an ant reacts by from
20 to 40 possible responses to any stimuli16. Yet this simple set of carefully
selected reactions lead to a vital ant-colony, which has emergent properties:
forages, fights, nurse young, maintain colony etc. Currently, we have no other
vital alternatives to observe self-organization and emergence than to perform a
real experiment either in situ or in vivo, or run an in silico experiment. Often,
it is difficult or ethically impossible to perform real experiments in vivo and
that is where simulations become a very important part of biomedical research.
When we look at a living cell by an eye of a trained CSs researcher, we see
processes represented by DNA, RNAs, proteins, lipids, carbohydrates,
ribosomes, organelles, cytoskeletons, membranes, and other cellular
structures. Their mutual interactions are governed via signaling molecules,
proteins, mechano-transduction as a governing-rule. Each functioning cell we
see as an emergent structure arising from all those processes via their mutual
interactions. The same is true for the next higher organizational-level, i.e. for
tissues that comprise of cells and their mutual signaling by molecules,
hormones and mechano-transduction that constitute a new governing-rule.
Cells decide which genes are switched on/off what leads to creation of
different cell types and tissues as emergents. Tissues create organs as a new
level of emergents that are mutually sending information through nerves,
hormones and molecules, which defines an additional governing-rule. Simply
said, we are dealing with a whole cascade of different emergents and their
mutual interactions, which are different on various levels (Figure 3).
Governing-rules vary at different levels of emergents: genes for cells;
signaling molecules, hormones, and mechano-transduction for tissues;
hormones and nervous system for organs; brain and hormones for bodies.
Complex systems provide a brand new approach describing observed
phenomena compared to classical methods such as differential equations,
statistics and probability. CSs are currently applied for example in so different
fields, as are physiology (reveals new physiological dependencies from
medical data streams), ECG22,23, EEG24,25, gait26, apnea27, and
sociology/ecosystems (self-organization of large ensembles of individuals) 17,18.
They provide guidelines for the development of new methods. Entropy is used
to measure information content within these systems. CSs describe discrete
events (protein-protein, chemical-chemical, chemical-protein, which can be
averaged (e.g. LBM gives Navier-Stokes Eq.). CSs are applied in multi-scale
8
modelling (multicellular growth systems28, aneurysm development29, RBC vs
blood-vessel wall interactions30 etc.), bio-fluid flows, bio-mechanics 31, bio-
chemistry, and pattern recognition32.

COMPUTATIONAL METHODS DEVELOPED WITHIN COMPLEX

SYSTEMS AND THEIR APPLICATIONS IN BIOLOGY AND
MEDICINE
The number of computational methods developed within CSs is quite high
and it is continuously increasing. The same methods are often independently
redeveloped within diverse scientific fields. It is often hard to recognize, at
least for some of them, that those methods belong to CSs because they do not
classify themselves as CSs. Hence, it is crucial to get the understanding of the
core of CSs to have a kind of navigational map. According to the authors, CSs
methods and tools can be split roughly into the following classes: (i)
modelling, (ii) determining properties of CSs, (iii) and their classification. A
model is a mathematical representation of an observed natural phenomenon
using a specific method, and simulation is its evaluation using a computer.
Classification is a decision process, which leads to a conclusion about the type
of observed phenomenon; its performance is usually lower than 100%, it
means that some cases remain undecidable. A classification can distill CS’s
general properties from measured data (e.g., ECG, EEG, etc.) Currently, there
exist three main branches explaining the core of CSs models: (i) cellular
automata (CAs)4,12,15, (ii) agent based models (ABMs)13,18,19,33, (iii) and Lattice-
Boltzmann Method (LBM)34-36. Other CSs methods are derived directly or
indirectly from them. The range of methods and tools that serve to classify
CSs is quite wide as well; it can be roughly divided along the following lines:
CS measures quantify the complexity of signals or complicated systems
composed by many parts by just one number; machine learning reveals data
dependences unachievable by other methods (curves, equations, and statistics);
and finally, data mining, which represents even more sophisticated
computerized methods compared to machine learning (e.g. Artificial
Intelligence – AI) (Table 1).
Cellular Automata (CAs) – represent the oldest computational method used
to model CSs. This method is due to its inherent, massive parallelism suitable
for description of systems created by fixed, locally, and mutually interacting
entities4,12,15. CAs are suitable for modelling of disease spread within
populations, excitable media (e.g. heart arrhythmia), pattern formation, pattern
recognition, bacterial colony growth, cancer growth37,38 and many others. One
of their first medical applications were the simulations of heart arrhythmias
where, for example, an excitable medium can under certain conditions (e.g.,
dispersion of conductivity through ventricular walls, dispersion of the action
potential height, infarct tissue, and conductivity disorders) create a spiral that
is present within human heart ventricles. Spirals are the cause of ventricular
tachycardia and other lethal ventricular arrhythmias. The biggest drawbacks of
CAs modelling and simulations are their inherent anisotropy due to presence
9
of a spatial (2D or 3D) lattice discretizing space and the discretization itself 39.
It often causes unrealistic artifacts in the resulting simulation, which can
usually be only partially compensated39. Tumors and their growth represent
one of the most studied medical applications of Cas 40. They usually develop to
quite complex structures that are very difficult to model and simulate due to
simultaneous operation of many interdependent processes within them:
growth, angiogenesis, fingering, invasion, metastasis, etc.
Historically, CAs represent predecessors of Lattice Gas Models (LGM) (that
later redeveloped in LBM), they were applied in spatial Theory of Games
(ToGs)(41-43), and they sit behind the concept of dynamic Complex Networks
(CXNs)(44,45). Despite CAs simplicity, they are capable of generating endless
complexity3,46 and they deserve their place as a CS model of the first choice in
many cases even nowadays. The perfect knowledge of CAs design enables
researchers to simplify more elaborated types of CSs models. CAs often serve
as a testing bed for such more advanced models. A list of CSs methods
presented in this section and their characteristics with examples of use in
medicine and biology is provided in Table 1.
Agent Based Models (ABMs)13,19,33,35,47 – this method is suitable for
description of systems containing movable entities (people, movable vascular
walls, cells, proteins etc.). Immune system48, immune defense, host-pathogen
interactions49, and blood flow models29,30,50 including interaction with vascular
walls29 are often built using ABM. Let us imagine a diseased tissue that is
gradually perfused by immune cells, which are moving through the tissue and
react with it. Classical modelling techniques based on equations (e.g. PDEs &
FEMs) are incapable of describing movable particles and movable boundaries
in the tissue contrary to ABMs. The disadvantage of ABMs is the requirement
for supercomputers to simulate reasonably large tissue areas. It is also not easy
to identify model parameters for real biological structures. One of the main
causes of death in USA and Europe is ductal carcinoma in situ. Its good
understanding via agent-based modelling oriented to individual patients51 can
lead to the ability of practitioners to predict evolution of an individual
carcinoma; and can help to make precise clinical predictions and increase
survival rates. This is a new stream of research towards the individual
oriented, predictive medicine.
Complex Networks (CXNs) – this method is very suitable for mathematical
description of processes operating on graphs and networks 44,45,52,53. Generally,
networks of dynamically communicating processes are ubiquitous in biology
and medicine: ecosystems, societies, metabolic networks, protein-protein
interactions, signaling cascades, gene regulatory networks, etc. 54,55. The ability
to manipulate with operating networks, measure their properties and predict
their outcomes pursue medical research in the new millennium 55-61. CXNs are
massively used to scan dependences between phenotypes of diseases and
diseased genes (naturally changed genes within populations) from huge
databases without the necessity to perform any experiments in the laboratory.
CXNs serve as a background of Networked Medicine54,55,60,62. The
disadvantages include the need of working with millions of electronic cards of
10
patients (coming from extra-large hospitals and often insurance companies)
and the requirement for the use of extra-large computational facilities.
Nevertheless, those disadvantages are relatively small when compared to
several thousands expensive knockout studies necessary to achieve the same
results using standard approaches. This means that mathematics can search
through data that we already have due to the availability of large numbers of
naturally diseased (or ‘knockout’) genes in various alleles of human genome.
CXNs are very useful for description of heterogeneous processes operating
simultaneously. Glioblastoma heterogeneity can serve as a good example of a
CXN describing the influence of multiple cancer clones existing within
cancerous tissues. They often lead to cancer treatment resistance which is
typically targeted to a single (solitary) clone63,64.
Machine Learning (ML) – is a growing collection of computational
methods extending classical ways of searching for dependences among (many)
variables65,66. Here, dependencies are not in the form of curves and equations
but they are more abstract: neuronal networks, random forests, Bayesian
networks, K-means clustering algorithm, support vector machines, etc. The
classification of arrhythmias from HRV demonstrated the necessity to use ML
techniques to achieve clinically relevant accuracy, specificity, and sensitivity.
In general, ML techniques enable to uncover hidden dependencies among data
that are linked in unexpected ways. There is a number of payed and free
computational tools (e.g. Weka, Python). The biggest disadvantage is that ML
techniques often do not allow the application of reverse engineering to dissect
the influence of each component that enters the analysis, e.g. neuronal
networks. ML motivate development of even more general computational
techniques that falls under the arms of Data Mining (DM) techniques. See a
list of the major computational methods developed within complex systems
that are used in biology (Table 1). The drawback of ML is the inability to
represent learned dependencies in a human-readable form! That somehow
impedes the use of ML in medicine. It can also be used to pave the path and to
narrow the search space, for more conventional approaches before ML
techniques in readable forms will be developed. For example, ML enables to
screen huge databases of compounds for simultaneous targeting of different
surface proteins—exactly as it was done for bird influenza with H1 and N1
targes67. Multiple targeting diminishes the chances of influenza to create
resistance.
Complex Systems Measures (CSMs) – those methods serve as a toolbox
enabling quantification and measuring various properties of complex systems.
CSs are very difficult to measure by standard techniques developed in other
fields. Most CSMs are based on the notion of entropy originally developed in
statistical physics, later applied in deciphering of encrypted messages (called
information entropy), and finally applied to CSs (Footnote 2). All previously
2 Entropy, i.e. the information content, of the flat line (nothing happens) is equal to zero. Entropy
increases as the complexity of the curve increase, i.e. as the curve becomes more complicated. Entropy
achieves its highest value for the white noise (it means entropy changes, i.e. jumps up and down, in a
completely random manner). Entropy of all other curves, including those created by CSs, lie between
those two extremal values: the flat line and the random one.
11
described methods except ML are used to model systems whereas CSMs are
used to quantify and measure their properties. CSMs enable comparison of
naturally observed CSs and their artificially made counterparts. For example,
CSMs are very useful in studying, quantifying and comparing physiological
signals: ECG22, EEG24, respiration27, muscle contractions, gait26 etc. ECGs of
young and healthy people tend to have a high complexity whereas hearts of
older and ill people have lower complexity22. The complexity of ECGs is
inversely associated with mortality. CSMs are giving information about the
overall behavior of the system; they are not useful for studies of fractional
parts of the system. For example, the cited work deals with a precise
determination of depth of anesthesia, introducing a special
electroencephalographic (EEG) measure, which plays a key role in the
assessment of the effect of sedatives. Entropies are quite effective in such
tasks as is demonstrated in this paper where an entropy measure enables to
produce an index measuring the EEG effect of the applied GABAergic drugs68.
Current major computational methods and approaches are listed in Table 3.
There is possible to get a wide overview of all methods used in all scientific
disciplines. It is evident that biology is using those most developed methods
and pursues a development of even more elaborated computational tools. For a
clear explanation of importance or frequencies of used computational methods
with dependence of description level within human body, please inspect
Table 4.

Table 3 Existing Major Computational Methods and Approaches. Documented is name of method,
computational methods used to evaluate it, whether analytical method(s) giving the exact solution exists
(it is very important for calibration of results), and what is the method used for. For easy calibration of
any simulations, it is necessary to know if general/special theory exists; signs [±/±] in the column “Name
of Method” display it.

Name of
Computational Methods Used What it is used for
Method

Partial Finite element method (FEM), f. Spatial evolution of quantities, e.g., diffusion,
Differential volume m. (FVM) and f. difference stresses and deformation fields within
Equations m. are discretizing partial differential materials (re-meshing necessary if boundaries
(PDEs)5-7,87 equations87,88. moves) [e.g. drug content in different parts of
[+/+] the body, e.g. describe strain in bones,
muscles].

Ordinary Finite difference method (FDM) is Simulation of temporal evolution of quantities

Differential discretizing ordinary differential without spatial information (e.g. the total drug
Equations equations (Euler, Runge-Kutta, etc. content in the body)
(ODEs)(ref. 89)
methods)(ref. 8,87).
[+/+]

Monte Carlo Repeated random sampling to obtain Extremely useful for simulation of movable
Simulations results90. domain borders. A drawback is non-parallel
(ref. 90)
(MCs) [-/ evaluations of lattice sites and unsuitable for
+] models working thermodynamically far-from-
equilibrium91.

12
Molecular Solve Newton’s equations of motion Simulation of movements and interactions of
Dynamics using averaged quantum potentials atomic ensembles, e.g., proteins, drugs,
(MD)(ref. 92) [-/ (derived from quantum mechanics)(ref. chemistry; solid-state physics; DNAs.
92)
+] .

Ab Initio The atomic potentials are directly True quantum physical computations of
quantum defined by Quantum Mechanics93. molecular structures; very precise but
chemistry extremely computationally expensive.
method93
[-/+]

Agent-Based Interactions among simulated entities Off-lattice models describing behavior of cell
Models using autonomous agents according structures, cells, tissues, social interactions
(ABMs)(ref. 18,33) physically relevant rules18,33. (escape behavior18, economy).
[-/+]

Cellular Simulated using simple governing- In biology: cells, tissues, social interactions,
Automata rules on discretized space & time. chemical interactions (Belousov-Zhabotinski
(CAs)(ref. 4,12,38) reaction), infections (AIDS, STDs, bacterial,
[-/-] viral), and excitable media. In computer
science: coding, decoding.

Multi-Scale Different computational Potentially encompass all levels of the system

Models models/methods are operating under consideration; each level applies
(MSMs)(ref. 80,85) simultaneously on different scales of different computational method operating
[-/-] space and/or time. Finer simulation with different speed. We can understand it as
scales are applied only in a computational ‘Russian doll’: each part is
dynamically changing regions what different.
save huge amounts of the
computational time.

Lattice- Newtonian fluid with collisions Simulates fluid flows (blood, urine, lymph,
Boltzmann (propagating & colliding fictive extracellular liquid), mechanical interaction,
Methods particles on discrete mesh). Belongs without need of re-meshing. Deals with
(LBMs)(ref. 35)
to computational fluid dynamics complex boundaries; involves microscopic
[-/-] methods35. interactions and mixtures of liquids.

Complex Small-worlds and scale-free networks Information flows, dependencies among

Networks often best represent behavior and entities, evolution of complicated structure as,
(CXNs)(ref. 44,60-
properties of real networks44. e.g. cells, tissues, organs, ecosystems, etc. It
62)
involves networked medicine45,54,60-62,
[-/+] metabolic, gene regulatory, brain, social, and
technological networks.

Lattice Gas A variant of CA; Navier-Stokes
Automata equations can be derived from LGA
(LGA)(ref.94) as averages. Lattice defines six
[-/+] directions where ’particles’ travel.
They collide according defined
governing-rules94.
Fluid flow, currently less used. LGAs were
very important for development of newer
methods, e.g., LBM; they open new directions
in research. They operate on square and
hexagonal grids.

Theory of It studies conflict and cooperation Used to model microbial and social
Games (ToG) between intelligent, rational, fully interactions; social and economic
(ref. 41)
[-/+] informed decision-makers. applications.
Originally, it employed pay-off tables
to decide interaction outcomes
between entities.

13
LIMITATIONS OF COMPLEX SYSTEMS
CSs are subjected to a constant development and they still suffer from a lack
of theories describing and predicting their behavior. So far, we do have a
handful of predictive tools, mainly for some special regimes of CSs. Usually,
the only way to gain knowledge about behavior of CSs is to observe them in
situ, in vivo, or to simulate them in silico. That inevitably brings several
problems in the in silico case: the necessity to develop a reliable model, its
implementation, the use of supercomputers, and the ability to interpret results.
None of those is easy, especially when there is existing a lack of knowledge
about design of models in so far unexplored CSs research areas including
biology and medicine. Simulations of CSs and their analysis typically require
huge computational power. Often, these methods are not settled down and
their use requires an experienced mathematician. Validation of results is often
difficult due to missing theories; hence, experiments serve for validation. CSs
modelling requires a broad knowledge of mathematics, computer science,
numerical mathematics, statistics, and fields in which they are applied.

Table 4 The organizational levels of living organisms were scanned with respect to mathematical
methods used to describe them. WebOfKnowledge database was used as on Jan 2017. Logical operator
AND was used to join given line and column terms what produced the number in given cell. Lines
represent organizational levels, columns represent mathematical method used, and each cells is
displaying the numbers of hits of papers published with the given search combination.

PDE ODE
Description partial Theor
ordin MC MD Ab ABM CA MS LBM
Level (lines) differen y of
ary “Mo "mole Initio agent "cellu "multi lattice
vs tial Games
differe nte cular "Ab based lar scale Boltz
Computational theory
ntial Carlo dyna initio model autom model mann
Method of
equatio equati ” mics" " * at*" *" model
(columns) games
n* on*

Ecosystem
83 123 728 15 8 579 280 23 5 126
ecosystem*

Body
(medicine OR
8 13 264 61 24 128 10 8 4 8
biology) AND
body

Organs
(medicine OR
42 52 449 181 62 344 58 24 7 44
biology) AND
organ*

Tissues
(medicine OR
39 30 646 81 13 326 29 27 3 9
biology) AND
tissue*

Cells
(medicine OR
143 242 424 579 74 936 250 62 11 52
biology) AND
cell*

14
Proteins,
Organelles
(medicine OR
34 112 259 1209 179 385 18 19 3 8
biology) AND
(protein* OR
organelle*)

Molecules
(medicine OR
26 45 119 477 139 209 8 8 0 4
biology) AND
molecule*

Atoms
(medicine OR
3 2 185 472 122 29 1 2 1 1
biology) AND
atom*

FUTURE DEVELOPMENT OF COMPLEX SYSTEMS

CSs are understood as the mathematics of 21st century. They will change
whole disciplines including medicine and biology, and create new ones.
Current state-of-the-art of CSs has a great potential in description of biomatter
(Table 4). Multi-scale models are becoming a routine way of research. They
enable: to study holistic medicine on a solid mathematical background,
explorations of massive parallelism/concurrency operating within biomater,
medical development of effective yet least harmful treatments of many
diseases, to study biomatter as the whole and not only in weakly interrelated
bits and pieces. CSs has a big potential in prediction of serious diseases
(preventive medicine), in better understanding and treating currently less
treatable conditions, via exploring massively distributed regulatory
mechanisms, e.g. in septic shock and multi-organ failure syndrome.
As mentioned, CSs description of diseases offers a brand new approach to
disease treatment. In future medicine, a disease operating on one level could
be influenced by an intervention on another level(s). If done correctly, the
intervention can then be performed within physiological levels contrary to
many interventions carried out in vivo nowadays. To elucidate this process, let
us build a virtual model of a cell: not topologically but in the form of
networks. Contemporary science is gradually building knowledge about
various functional networks operating within cells: DNA, GRN, metabolic,
signaling, protein-protein interaction, etc.52,54,59-62,69. For example, a protein-
protein network consist of proteins as nodes and existing protein-protein
interactions as links. It is possible to merge all those networks together and to
make a network of networks describing everything what is occurring in the
cell. The idea is to control a specific node of this network of networks, the
diseased one, indirectly via distant nodes of the very same network (Figure 4).
In another words, possibly several upstream nodes influence the diseased
node, which is operating out of physiological/functional regime, where the
influence is carried out within physiological levels of those intervening nodes.

15
In this way, the crucial problem of drug side effects can be resolved. Possibly,
at least in some cases, the need to use any drug can be overcome.

Figure 4: A simplified model of a network of networks describing everything what is

undergoing in the cell. The diseased node is controlled indirectly via possibly distant
intervention nodes of the network. Several upstream nodes affect the diseased node, which is
operating out of physiological/functional regime, where the influence is performed within
physiological levels of those intervention nodes.

This approach represents a promising way of how the future real and
functioning personalized medicine can be built. Each treatment could be
adjusted to a specific person and his/her current condition (even with daily
variations). This approach opens a completely new stream of research that will
look for imbalances within cell’s networks and treat diseases by diminishing
those imbalances: it will work on all levels of emergents. This is not definitely
easy task because we are dealing with emergent structures and current CSs
experiments and theory has only a handful of tools capable of it. From the
computational point of view, this task represents a great challenge to the
current state-of-the-art of CSs design and modelling. A promising perspective
seems to be the possibility to build automatized, computer driven therapies of
some life-threatening diseases that are incurable by slow-reacting usual
technologies involved in the therapy. Therefore, the automatized, fast and
precise systems could be designed in the way that would serve as a backup for
the cases where the first proposed approach fails.

CONCLUSIONS
This review shows the possibilities of Complex Systems (CSs) in the
description of observed biological and medical phenomena. Using a large
number of examples, CSs have demonstrated they are capable to describe
human body on many levels of its functioning (possibly on all of them at
16
once), and that they can describe those functional levels in health and disease.
CSs are thanks to the current fast technological development able to model,
predict and mathematically describe the laws and patterns of biological
systems behavior in physiological and non-physiological conditions.
Undoubtedly, we are approaching the moment when medicine will acquire
diagnostic and therapeutic tools based on CSs mathematical approaches. The
importance of these tools will be most likely increasing with time.

Acknowledgements: This study was supported by the National Sustainability

Program I (NPU I) Nr. LO1503 provided by the Ministry of Education Youth
and Sports of the Czech Republic.

Author Disclosure Statement: No competing financial interests exist.

Abbreviations

CS Complex system
CA Cellular Automaton
ABM Agent-based model
LBM Lattice Boltzmann method
ToG Theory of games
LGM Lattice-gas method
CXN Complex network
NB Networked biology
NM Networked medicine
CSM Complex system measure
ML Machine learning
DM Data mining
MSM Multi-scale model
ODE Ordinary differential equation
PDE Partial differential equation
FEM Finite element method
FVM Finite volume method
FDM Finite difference method
MCM Monte Carlo method
MD Molecular dynamics

Search strategy and selection criteria: Our search strategy was focused to
complex systems and medicine. Scientific articles, only in English language,
from 1974 to April 2017 were searched using the Web of Science database.
Each complex systems modelling subfield was searched separately: e.g.
cellular automata, agent based models, etc. In the Table 4 are provided
examples of many important searching criteria with respect to subfields of

17
complex systems. Due to the large number of searched criteria, they can not be
explicitly written but can be easily found in the text of the review.

References
1. Kahan M, Gil B, Adar R, Shapiro E. Towards molecular computers that operate in a biological
environment. Physica D. 2008;237(9):1165-1172.
2. Weinberg BH, Pham NTH, Caraballo LD, et al. Large-scale design of robust genetic circuits with
multiple inputs and outputs for mammalian cells. Nat Biotechnol. 2017;35(5):453-462.
3. Gardner M. Mathematical games: The fantastic combinations of John Conway's new solitaire game
“life”. Sci Am. 1970;223(4):120-123.
4. Hoekstra AG, Kroc J, Sloot PMA, eds. Simulating Complex Systems by Cellular Automata
(Understanding Complex Systems). Berlin, Heidelberg:Springer-Verlag. 2010.
5. Polianin AD, Zaitsev VF. Handbook of nonlinear partial differential equations. 2nd ed. Boca Raton,
London, New York: Chapman & Hall/CRC; 2011:1912.
̈
6. Roubicek T. Nonlinear partial differential equations with applications. 2nd ed. Basel: Birkhauser;
2013:476.
7. Polianin AD, Zaitsev VF, Moussiaux A. Handbook of first order partial differential equations. London,
New York: Taylor & Francis; 2001:520.
8. Bradie B. A Friendly Introduction to Numerical Analysis. Upper Saddle River, New Jersey: Pearson
Education / Prentice Hall; 2005:984.
9. Hartmann AK. Big Practical Guide to Computer Simulations. 2 nd ed. Singapore; New Jersey: World
Scientific Publishing Co.; 2015:484.
10. Kroese DP, Taimre T, Botev ZI. Handbook for Monte Carlo methods. John Wiley & sons; 2011:772.
11. Nolte DD. Introduction to Modern Dynamics : Chaos, Networks, Space and Time. Oxford New York,
NY: Oxford University Press; 2015:432.
12. Ilachinski A. Cellular Automata: A Discrete Universe. World Scientific Publishing Co., 2001:842.
13. Ilachinski A. Artificial War: Multiagent-Based Simulation of Combat. World Scientific Publishing
Co., 2004:784.
14. Hoekstra AG, Kroc J, Sloot PMA. Introduction to Modeling of Complex Systems Using Cellular
Automata. In: Kroc J, Sloot PMA, Hoekstra AG, eds. Simulating Complex Systems by Cellular
Automata. Berlin, Heidelberg: Springer, 2010:1-16.
15. Adamatzky A., ed. Game of Life Cellular Automata. London: Springer Verlag, 2010.
16. Hölldobler B, Wilson EO. Journey to the Ants: A Story of Scientific Exploration: Cambridge:
Harvard Univ. Press, 1994:228.
17. Prelec D, Seung HS, McCoy J. A solution to the single-question crowd wisdom problem. Nature.
2017;541:532-535.
18. Helbing D, ed. Social Self-Organization: Agent-Based Simulations and Experiments to Study
Emergent Social Behavior (Understanding Complex Systems). Berlin: Springer Verlag; 2012.
19. Helbing D, Balietti S. How to Do Agent-Based Simulations in the Future: From Modeling Social
Mechanisms to Emergent Phenomena and Interactive Systems Design. In: Social Self-Organization,
Helbing D, ed. Berlin: Springer Verlag, 2012:25-70.
20. Nagel K, Schreckenberg M. A cellular automaton model for freeway traffic. J Phys I.
1992;2(12):2221-2229.
21. Maukonen J, Saarela M. Human gut microbiota: does diet matter? Proc Nutr Soc. 2015;74(1):23-36.
22. Voss A, Kurths J, Kleiner HJ, et al. The application of methods of non-linear dynamics for the
improved and predictive recognition of patients threatened by sudden cardiac death. Cardiovasc Res.
1996;31(3):419-433.
23. Acharya UR, Joseph KP, Kannathal N, et al. Heart rate variability. In: Acharia UR, Suri JS, Spaan
JAE, Krishnan SM, eds. Advances in Cardiac Signal Processing. Berlin, heidelberg: Springer, 2007:121-
165.
24. Acharya UR, Fujita H, Sudarshan VK, et al. Application of entropies for automated diagnosis of
epilepsy using EEG signals: A review. Knowl-Based Syst. 2015;88:85-96.
18
25. Lee UC, Blain-Moraes S, Mashour GA. Assessing levels of consciousness with symbolic analysis.
Philos T R Soc A. 2015; 373(2034) 20140117.
26. Costa M, Peng CK, Goldberger AL, Hausdorff JM. Multiscale entropy analysis of human gait
dynamics. Physica A. 2003;330(1-2):53-60.
27. Hornero R, Alvarez D, Abasolo D, et al. Utility of approximate entropy from overnight pulse
oximetry data in the diagnosis of the obstructive sleep apnea syndrome. IEEE T Bio-Med Eng.
2007;54(1):107-13.
28. Bellomo N, Bellouquid A, Nieto J, Soler J. Multiscale Biological Tissue Models and Flux-Limited
Chemotaxis for Multicellular Growing Systems. Math Mod Meth Appl S. 2010;20(7):1179-1207.
29. Bernsdorf J, Wang D. Non-Newtonian blood flow simulation in cerebral aneurysms. Comput Math
Appl. 2009;58(5):1024-1029.
30. Zhang JF, Johnson PC, Popel AS. An immersed boundary lattice Boltzmann approach to simulate
deformable liquid capsules and its application to microscopic blood flows. Phys Biol. 2007;4(4):285-95.
31. Nedelec F. Computer simulations reveal motor properties generating stable antiparallel microtubule
interactions. J Cell Biol. 2002;158(6):1005-1015.
32. Studholme C, Hill DLG, Hawkes DJ. An overlap invariant entropy measure of 3D medical image
alignment. Pattern Recogn. 1999;32(1):71-86.
33. Bonabeau E. Agent-based modeling: Methods and techniques for simulating human systems. P Natl
Acad Sci USA. 2002;99:7280-7287.
34. Aidun CK, Clausen JR. Lattice-Boltzmann Method for Complex Flows. Annu Rev Fluid Mech.
2010;42:439-472.
35. Guo Z, Shu C. Lattice Boltzmann method and its applications in engineering. Hackensack, New
Jersey: World Scientfic; 2013:404.
36. Benzi R, Succi S, Vergassola M. The lattice Boltzmann equation: theory and applications. Phys Rep.
1992;222(3):145-197.
37. Kansal AR, Torquato S, Harsh GR, et al. Simulated Brain Tumor Growth Dynamics Using a Three-
Dimensional Cellular Automaton. J Theor Biol. 2000;203(4):367-382.
38. Bellomo N, Li NK, Maini PK. On the foundations of cancer modelling: selected topics, speculations,
and perspectives. Math Mod Meth Appl S. 2008;18(4):593-646.
39. Kroc J. Influence of Lattice Anisotropy on Models Formulated by Cellular Automata in Presence of
Grain Boundary Movement: A Case Study. In: Pokluda J, ed. Materials Structure & Micromechanics of
Fracture. Mater Sci Forum. 2005;482:195-198.
40. Lowengrub JS, Frieboes HB, Jin F, et al. Nonlinear modelling of cancer: bridging the gap between
cells and tumours. Nonlinearity. 2010;23(1):R1-R9.
41. Perc M, Szolnoki A. Coevolutionary games-A mini review. BioSystems. 2010;99(2):109-125.
42. Kiraly B, Szabo G. Evolutionary games with coordination and self-dependent interactions. Phys Rev
E. 2017;95(1):12303.
43. Szabo G, Fath G. Evolutionary games on graphs. Phys Rep. 2007;446(4-6):97-216.
44. Albert R, Barabasi AL. Statistical mechanics of complex networks. Rev Mod Phys. 2002;74(1):47-
97.
45. Dehmer M, Mowshowitz A. A history of graph entropy measures. Inform Sciences. 2011;181(1):57-
78.
46. Wolfram S. Statistical-Mechanics of Cellular Automata. Rev Mod Phys. 1983;55(3):601-644.
47. Cilfone NA, Kirschner DE, Linderman JJ. Strategies for Efficient Numerical Implementation of
Hybrid Multi-scale Agent-Based Models to Describe Biological Systems. Cell Mol Bioeng.
2015;8(1):119-136.
48. Cappuccio A, Tieri P, Castiglione F. Multiscale modelling in immunology: a review. Brief Bioinform.
2015;17(3):408-418.
49. Bauer AL, Beauchemin CAA, Perelson AS. Agent-based modeling of host-pathogen systems: The
successes and challenges. Inform Sciences. 2009;179(10):1379-1389.
50. Reasor DA, Jr., Clausen JR, Aidun CK. Coupling the lattice-Boltzmann and spectrin-link methods
for the direct numerical simulation of cellular blood flow. Int J Numer Meth Fl. 2012;68(6):767-781.

19
51. Macklin P, Edgerton ME, Thompson AM, Cristini V. Patient-calibrated agent-based modelling of
ductal carcinoma in situ (DCIS): From microscopic measurements to macroscopic predictions of clinical
progression. J Theor Biol. 2012;301:122-140.
52. Ravasz E, Somera AL, Mongru DA, et al. Hierarchical organization of modularity in metabolic
networks. Science. 2002;297(5586):1551-1555.
53. Newman MEJ. The Structure and Function of Complex Networks. SIAM Rev. 2003;45(2):167-256.
54. Barabasi A-L, Oltvai ZN. Network biology: understanding the cell's functional organization. Nat Rev
Genet. 2004;5(2):101-113.
55. Liao JC, Boscolo R, Yang YL, et al. Network component analysis: Reconstruction of regulatory
signals in biological systems. P Natl Acad Sci USA. 2003;100(2-6):15522-15527.
56. Gao JX, Buldyrev SV, Stanley HE, Havlin S. Networks formed from interdependent networks. Nat
Phys. 2012;8(1):40-48.
57. Gao JX, Barzel B, Barabasi A-L. Universal resilience patterns in complex networks. Nature 2016,
530:307-312.
58. Shen Y, Liu J, Estiu G, et al. Blueprint for Antimicrobial hit discovery targetin metabolic networks. P
Natl Acad Sci USA. 2010; 107(3):1082-1087.
59. Vidal M, Cusick ME, Barabasi A-L. Interactome networks and human disease. Cell. 2011;
144(6):986-998.
60. Barabasi A-L, Gulbahce N, Loscalzo J. Network medicine: a network-based approach to human
disease. Nat Rev Genet. 2011;12(1):56-68.
61. Gustafsson M, Nestor CE, Zhang H, et al. Modules, networks and systems medicine for
understanding disease and aiding diagnosis. Genome Med. 2014;6(10):82.
62. Barabasi AL. Network Medicine - From Obesity to the "Diseasome''. New Engl J Med.
2007;357(4):404-407.
63. Bonavia R, Inda MM, Cavenee WK, Furnari FB. Heterogeneity Maintenance in Glioblastoma: A
Social Network. Cancer Res. 2011;71(12):4055-4060.
64. Inda MM, Bonavia R, Seoane J. Glioblastoma Multiforme: A Look Inside Its Heterogeneous Nature.
Cancers. 2014;6(1):226-239.
65. Cleophas TJ, Zwinderman AH. Machine Learning in Medicine - a Complete Overview. Cham:
Springer; 2015:516.
66. Deo RC. Machine Learning in Medicine. Circulation. 2015;132(20):1920-1930.
67. Chang SS, Huang HJ, Chen CYC. Two Birds with One Stone? Possible Dual-Targeting H1N1
Inhibitors from Traditional Chinese Medicine. PLoS Comput Biol. 2011;7(12) e1002315.
68. Olofsen E, Sleigh JW, Dahan A. Permutation entropy of the electroencephalogram: a measure of
anaesthetic drug effect. Brit J Anaesth. 2008;101(6):810-821.
69. Shen Y, Liu J, Estiu G, et al. Blueprint for antimicrobial hit discovery targeting metabolic networks.
P Natl Acad Sci USA. 2010;107(3):1082-1087.
70. Kirkwood BR, Sterne JAC. Essential medical statistics. 2nd ed. Malden, Mass.: Willey Blackwell
Science, 2003:512.
71. Bender EA. An introduction to mathematical modeling. Mineola, N.Y.: Dover Publications;
2000:272.
72. Haken H. Advanced Synergetics : Instability Hierarchies of Self-Organizing Systems and Devices.
Berlin, New York, Heidelberg, Tokyo: Springer-Verlag, 1983:356.
73. Haken H. Synergetics : An introduction. 3rd ed. Berlin, Heidelberg: Springer, 1983:390.
74. Mandelbrot B. The fractal geometry of nature. New York: W.H. Freeman; 1982:480.
75. Novak MM, ed. Thinking in Patterns : Fractals and Related Phenomena in Nature. World Scientific,
2004:336.
76. Bak P. How nature works : the science of self-organized criticality. New York: Springer, 1996:212.
77. Bak P, Tang C, Wiesenfeld K. Self-organised criticality: An explanation of 1/f noise. Phys Rev Lett.
1987;59(4):381-384.
78. Osborne JM, Fletcher AG, Pitt-Francis JM, et al. Comparing individual-based approaches to
modelling the self-organization of multicellular tissues. PLoS Comput Biol. 2017;13(2) e1005387.

20
 79. Kim YH, Xu X, Lee JS. The Effect of Stent Porosity and Strut Shape on Saccular Aneurysm and its
Numerical Analysis with Lattice Boltzmann Method. Ann Biomed Eng. 2010;38(7):2274-2292.
80. Warshel A. Multiscale Modeling of Biological Functions: From Enzymes to Molecular Machines
(Nobel Lecture). Angew Chem Int Edit. 2014;53(38):10020-10031.
81. Witten IH, Frank E, Hall MA, Pal CJ. Data Mining : Practical Machine Learning Tools and
Techniques. 4th ed. Morgan Kaufmann; 2016.
82. Fernandez-Llatas C, García-Gómez JM. Data Mining in Clinical Medicine. New York, NY: Humana
Press; 2015:270.
83. De S, Hwang W, Kahl E. Multiscale Modeling in Biomechanics and Mechanobiology. London,
Heidelberg, New York, Dordrecht: Springer; 2015:286.
84. Kamerlin SCL, Warshel A. Multiscale modeling of biological functions. Phys Chem Chem Phys.
2011;13(22):10401-10411.
85. Steinhauser MO. Computational Multiscale Modeling of Fluids and Solids : Theory and
Applications. 2nd ed. Berlin, Heidelberg: Springer; 2017:405.
86. Kamerlin SCL, Vicatos S, Dryga A, Warshel A. Coarse-Grained (Multiscale) Simulations in Studies
of Biophysical and Chemical Systems. Annu Rev Phys Chem. 2011;62:41-64.
87. Lee HJ, Schiesser WE. Ordinary and partial differential equation routines in C, C++, Fortran, Java,
Maple, and MATLAB. Boca Raton: Chapman & Hall/CRC; 2003:528.
88. Schiesser WE, Griffiths GW. A Compendium of Partial Differential Equation Models : Method of
Lines Analysis with Matlab. Cambridge, New York: Cambridge University Press; 2009:490.
89. Hartman P. Ordinary differential equations. 2nd ed. Philadelphia: Society for Industrial and Applied
Mathematics; 1987:632.
90. Rubinstein RY, Kroese DP. Simulation and the Monte Carlo method. 3rd ed. Hoboken, New Jersey:
John Wiley & Sons; 2017:414.
91. Kroc J. Application of Cellular Automata Simulations to Modelling of Dynamic Recrystallization. In:
Sloot PMA, Hoekstra AG, Tan CJK, Dongarra JJ, eds. Computational Science—ICCS 2002. Lect Notes
Comput Sci. 2002; 2329:773-782.
92. Griebel M, Knapek S, Zumbusch G. Numerical Simulation in Molecular Dynamics: Numerics,
Algorithms, Parallelization, Applications. Berlin, Heidelberg: Springer; 2007:476.
93. Jensen F. Introduction to Computational Chemistry. 3rd ed. Chichester, UK ; Hoboken, NJ: John
Wiley & Sons; 2017:664.
94. Succi S. The Lattice Boltzmann Equation: For Fluid Dynamics and Beyond. Clarendon Press;
2001:304.

Authors contributions: Kroc J was responsible for the design of the review,
manuscript drafting, literature search and critical review of the mathematical
part of the review, Balihar K designed the medical part of the review,
contributed to literature search, critical review of content and edited the
manuscript, Matejovic M obtained research funding, supervised and approved
the final manuscript.

21

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