Applied Artificial Intelligence, 29:353381, 2015

Copyright 2015 Taylor & Francis Group, LLC

ISSN: 0883-9514 print/1087-6545 online
DOI: 10.1080/08839514.2015.1016391

STELLAR-MASS BLACK HOLE OPTIMIZATION FOR BICLUSTERING

MICROARRAY GENE EXPRESSION DATA

R. Balamurugan, A. M. Natarajan, and K. Premalatha

Bannari Amman Institute of Technology, Erode, Tamil Nadu, India

 DNA microarray gene expression data analysis has provided new insights into gene function, dis-
ease pathophysiology, disease classification, and drug development. Biclustering in gene expression
data is a subset of the genes demonstrating consistent patterns over a subset of the conditions. The
proposed work finds the significant biclusters in large expression data using a novel optimization
technique called stellar-mass black hole optimization (SBO). This optimization algorithm is inspired
from the property of the relentless pull of a black holes gravity that is present in the Universe.
The proposed work is tested on benchmark optimization test functions and gene expression bench-
mark datasets, and the results are compared with swarm intelligence techniques such as particle
swarm optimization (PSO), and cuckoo search (CK). The experimental results show that the SBO
outperforms PSO and CK.

INTRODUCTION
Microarray technology attracts keen interest among the scientific
community and in industry. Through an analysis of gene expression data,
it is possible to learn the behavioral patterns of genes such as similar
behavior (Lockhart and Winzeler 2000). These patterns are used in the
medical domain to aid in more accurate diagnoses, treatment planning,
and drug discovery. DNA microarray enables researchers to analyze the
expression of many genes in a single experiment rapidly and in an efficient
manner. After the number of preprocessing steps, the low-level analysis of
a microarray can be represented as a numerical matrix. In this matrix, the
rows represent different genes and the columns represent experimental
conditions (Androulakis, Yang, and Almon 2007). Each element of the
matrix represents the expression level of a gene under a specific condition,

Address correspondence to R. Balamurugan, Department of Computer Science and Engineering,

Bannari Amman Institute of Technology, Erode, 638401, Tamil Nadu, India. E-mail: balacse05@
gmail.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/uaai.
354 R. Balamurugan et al.

FIGURE 1 Gene expression data matrix. Mark Reimers/Exploratory Analysis. Reproduced by permis-
sion of Mark Reimers/Exploratory Analysis. Permission to reuse must be obtained from the rightsholder.

which is represented by a real number. Figure 1 shows the gene expression

data matrix.
Analysis via clustering makes several assumptions that might not be com-
pletely adequate in all situations. First, the clustering can be applied to either
genes or conditions; it implicitly directs the analysis of a particular aspect of
the system. Second, clustering algorithms usually seek a disjoint set of ele-
ments, requiring that no gene or sample belongs to more than one cluster.
Biclustering is a simultaneous clustering of both the rows and columns of
gene expression data. The problem of partitioning of a set of objects into
k groups, which optimizes a stated condition of partition adequacy, is not
given as straightforward. Given n objects, the number of ways in which these
objects can be partitioned into k nonempty subsets (Liu 1968) is given in
Equation (1).
 
1   n
k
k
P (n, k) = (1)j k j (1)
k! j
j =0

Equation (2) approximates Equation (1):

kn
P (n, k) k nk e k 2 k. (2)
k!
Therefore, when the number of clusters k is not known in advance, then the
total number of valuations is given in Equation (3).

n
T (n) = P(n, k). (3)
k=1
 SBO for Biclustering Gene Expression Data 355

Finding significant biclusters in a microarray is a much more complex

problem than clustering (Divina and Aguilar-Ruiz 2006) and it is an NP-
hard problem (Tanay, Sharan, and Shamir 2002). The search space for
the biclustering problem is 2m+n , where m and n are the number of genes
and conditions, respectively. Usually m+n is more than 2000. The problem
of finding a consistent biclustering can be formulated as an optimization
problem. An optimization problem is a problem that determines the set of
potential solutions to the problem and defines one or more criteria that
measures the quality of an individual solution. Therefore, our goal is to
design and develop an algorithm to find coherent biclusters from gene
expression data by using an optimization technique. Hence, we design and
implement the biclustering based on the new optimization technique named
stellar-mass black hole optimization (SBO). There are probably millions of
stellar-mass black holes in our Milky Way galaxy. They trap stars, gas, plan-
ets, and anything else that would get up close. The strength of gravity of a
black hole depends on the mass of the object and the distance from it. When
it absorbs matter, the mass of the black hole is increased; during radiation
its mass is decreased. The optimization technique is deduced based on the
physics properties of a black hole.
The remainder of this article is organized as follows: in Biclustering
we describe the structure of biclusters, the problem statement, and a brief
introduction to related works in biclustering. The next section describes a
general overview of the black hole and SBO. A performance comparison of
the SBO with the PSO and CK is presented and a Biological Analysis Of
Biclusters, followed by our conclusion.

BICLUSTERING
Biclustering is a powerful analytical tool for the biologist. Biclustering
methods perform clustering in two dimensions simultaneously. That means
clustering methods derive a global model and biclustering algorithms pro-
duce a local model. When clustering is applied to gene expression data,
genes as well as conditions can be clustered. However, each gene in a
bicluster is selected using only a subset of the conditions, and each condition
in a bicluster is selected using only a subset of the genes. Biclustering, thus,
performs simultaneous clustering of both rows and columns of the gene
expression matrix instead of clustering these two dimensions separately.
In short, unlike clustering algorithms, biclustering algorithms can identify
groups of genes that show similar activity patterns under a specific subset of
the experimental conditions. Biclustering is used when one or more of the
following situations apply (Madeira and Oliveira 2004):
356 R. Balamurugan et al.

1. A single gene may participate in multiple pathways that may or may not
be coactive under all conditions.
2. Only a small set of the genes participate in a cellular process of interest.
3. An interesting cellular process is active only in a subset of the conditions.

Structure of Biclusters
Several types of biclusters have been described and categorized in the
literature, depending on the pattern exhibited by the genes across the exper-
imental conditions (Mukhopadhyay, Maulik, and Bandyopadhyay 2010).
Madeira and Oliveira (2004) have identified four major groups of structures
inside the submatrices:

1. Bicluster with constant value:

aij =

2. Bicluster with constant values on rows or columns:

   
aij = + i or aij = i and aij = + j or aij = j

3. Bicluster with coherent values:

aij = + i + j or aij = i j

4. Bicluster with coherent evolutions:

aih air ait aid or ahj arj atj adj

The bicluster sets are classified according to their relative structure

(Madeira and Oliveira 2004). This structure illustrates the arrangement
of the bicluster in full space. Figure 2 shows (a) a Single Bicluster, (b)
an Exclusive Row-and-Column Bicluster, (c) a Checkerboard Bicluster, (d)
an Exclusive-Rows Bicluster (e) an Exclusive Column Bicluster, and (f) an
Arbitrarily Positioned Overlapping Bicluster.

Problem Statement
The gene expression data can be represented as N M matrix A of
real numbers. Let G be a set of genes, C a set of conditions, and A(G, C)
the expression matrix, where G = {1,2, . . . , m} and C = {1,2, . . . , n}. The
element GExi,j of A(G, C) represents the expression level of gene i under
 SBO for Biclustering Gene Expression Data 357

FIGURE 2 Structures of biclusters.

condition j. The aim of biclustering is to extract the submatrix A(G, C )

of A(G, C), which is identified by gene subset G of G and condition subset
C of C. In general, the problem can be defined as finding large sets of
rows and columns (volume) such that the rows show unusual similarities
along the dimensions characterized by columns and vice-versa. The bicluster
cardinality or volume of bicluster is simply the product of the number of
genes and number of conditions in the bicluster. Our aim is to discover the
biclusters of maximum size with the minimum mean squared residue (MSR)
and maximum of gene variance (nontrivial).

Review of Related Works

In recent years, several biclustering methods have been suggested
for identifying local patterns in gene expression data. The biclustering
algorithms are classified into two different approaches: systematic search
algorithms and stochastic search algorithms, also called metaheuristic algo-
rithms. The first biclustering algorithm, called direct clustering, proposed
by Hartigan (1972) was one of the first works ever published on biclustering,
although it was not applied to gene expression data. Moreover, Cheng and
Church (2000) presented a first biclustering approach for gene expres-
sion data. Their algorithm adopts a sequential covering strategy in order
to return a list of n biclusters from an expression data matrix. It finds a sin-
gle bicluster at a time; repeated application of the method on a modified
matrix is needed to discover multiple biclusters. It results in highly overlap-
ping gene sets, which is a mere drawback. Tanay et al. (2002) introduced a
statistical-algorithmic method for bicluster analysis (SAMBA), a biclustering
algorithm that performs the simultaneous bicluster identification by using
358 R. Balamurugan et al.

exhaustive enumeration. In this method, the significant biclusters were iden-

tified by using a graph theoretic approach in which, because of its high
complexity, the number of rows that the bicluster may have is restricted.
Murali and Kasif (2003) intended to find conserved gene expression
motifs (xMOTIFs). They defined an xMOTIF as a subset of genes that is
simultaneously conserved across a subset of the conditions. In order to pre-
vent the algorithm from finding too small or too large biclusters, some
constraints on their size, conservation, and maximality is added to its for-
mal definition. Nevertheless, the algorithm uses prior knowledge about the
sample phenotypes. Ben-Dor et al. (2003) defined a bicluster as an order-
preserving submatrix (OPSM). The algorithm can be used to discover more
than one bicluster in the same dataset, even when they are overlapped. Even
so, the model concerns only the order of values and, thus, makes the model
quite restrictive. Bergmann, Ihmels, and Barkai (2003) proposed an iterative
signature algorithm (ISA) that provides a definition of biclusters as transcrip-
tion modules to be retrieved from the expression data. This method includes
data normalization and the use of thresholds that determine the resolutions
of the different transcription modules. However, there is no evaluation of
the statistical significance.
Mitra and Banka (2006) presented a multiobjective evolutionary algo-
rithm (MOEA) based on Pareto dominancy. Per the objective of this method,
it extracts of a large volume of bicluster to a given threshold, nevertheless,
the main drawback is that it consumes much time to find the best bicluster
and no overlapping is carried out. Divina & Aguilar-Ruiz (2006) presented
a sequential evolutionary biclustering (SEBI) approach. The term sequen-
tial refers to the way in which biclusters are discovered; only one bicluster
is obtained per each run of the evolutionary algorithm. An advantage of
SEBI is that a matrix of weights is used for the control of overlapped ele-
ments among the different solutions. Nevertheless, the main drawback of
this method is that it works well only for the special case of approximately
small biclusters. Liu and Wang (2007) introduced a maximum similarity
bicluster (MSB) algorithm. A process of iteratively removing the row or
column in the bicluster with the worst similarity score is performed until
there is one element left in the bicluster. MSB performs well for overlapping
biclusters and works well for additive biclusters; it works for the special case
of approximately square biclusters.
DiMaggio et al. (2008) proposed an approach that is based on the
optimal reordering of the rows and columns of a data matrix in order to
globally minimize a dissimilarity metric. Conversely to OPSM, this approach
allows for monotonicity violations in the reordering, but penalizes their con-
tributions according to a selected objective function. However, the main
drawback of this method is that the objective function extracts trivial solu-
tions. Liu et al. (2009) based their biclustering approach with the use of a
 SBO for Biclustering Gene Expression Data 359

PSO together with crowding distance as the nearest neighbor search strategy,
which speeds up the convergence to the Pareto front and also guarantees
diversity of solutions. Using PSO has the problems of dependency on initial
point and parameters, difficulty in finding their optimal design parameters,
and the stochastic characteristic of the final outputs. Coelho, de Franca,
and Zuben (2009) presented an immune-inspired algorithm for biclustering
based on the concepts of clonal selection and immune network theories
adopted in the original aiNet algorithm. It explores a multipopulation aspect
by evolving several subpopulations that will be stimulated to explore distinct
regions of the search space. Nevertheless, they consider only two different
objectives: MSR and volume; it might return trivial biclusters.
Ayadi, Elloumi, and Hao (2012) proposed as a pattern-driven neigh-
borhood search (PDNS) approach to the biclustering problem. It utilizes
fast greedy algorithms to generate diversified initial biclusters of reasonable
quality and a randomized perturbation strategy. This has the drawback that
it results in highly overlapping gene sets. Huang et al. (2012) proposed a
new biclustering algorithm based on the use of an evolutionary approach
(EA) together with hierarchical clustering. The parallel computing tech-
nology would be of great help to speed up the traditional EA framework,
but its disadvantage is that it extracts a small volume of biclusters. Roy,
Bhattacharyya, and Kalita (2013) introduced a CoBi: a pattern-based coreg-
ulated biclustering of gene expression data. It is used mainly for grouping
both positively and negatively regulated genes from microarray expression
data. However, it returns small size biclusters for large MSR value. Maatouk
et al. (2014) proposed an evolutionary biclustering algorithm based on the
new crossover method (EBACross). In order to avoid overlapping biclusters
and to increase the diversification of biclusters, a mutation operator used.
Nevertheless, it possibly takes a very long time on large inputs. Ayadi and
Hao (2014) presented a memetic biclustering algorithm (MBA) to discover
the negative correlation biclusters. It is used mainly for grouping both
positively and negatively regulated genes from microarray expression data.
Extracting small biclusters and quality of biclusters depending on threshold
values are the main issues of this approach.

STELLAR-MASS BLACK HOLE OPTIMIZATION

Preamble
Using Newtons Laws in the late 1790s, John Michell of England and
Pierre-Simon Laplace of France independently suggested the existence of
an invisible star. They calculated the mass and size that an object needs in
order to have an escape velocity greater than the speed of light, and around
a black hole there is a mathematically defined surface called the event horizon
360 R. Balamurugan et al.

that marks the point of no return. In 1915, the presence of black holes
was predicted through Einsteins theory of general relativity. In 1967, John
Wheeler, an American theoretical physicist, applied the term black hole
for the collapsed objects (Luminet 1998). A black hole is an object that is
so compact, its gravitational force prevents anything, including light, from
escaping. There are so many black holes in the universe that it is impossible
to count them. A black hole is born when an object becomes unable to with-
stand the compressing force of its own gravity. They form whenever massive
but otherwise normal stars die. The black holes cannot be seen but can be
detected by material being attracted to and falling into them.
The hole is called black because it absorbs all the light that hits the
horizon, reflecting nothing, just as a perfect blackbody in thermodynamics.
In this way, astronomers have identified and measured the mass of many
black holes in the universe through careful observations of the sky. All matter
in a black hole is squeezed into a region of infinitely small volume, called the
central singularity. The event horizon is an imaginary sphere that measures
how close to the singularity an object can safely get. Once an object has
passed the event horizon, it becomes impossible to escape: the object will
be drawn in by the black holes gravitational pull and will be squashed into
the singularity. The size of the event horizon is proportional to the mass of
the black hole. According to theory, there might be three different types of
black holes depending on their mass: Stellar, Supermassive, and Miniature as
shown in Figure 3. These black holes would have been formed in different
ways. Supermassive black holes, which can have a mass equivalent to billions
of suns, likely exist in the centers of most galaxies. The miniature black hole
would have a mass much smaller than that of a sun. The miniature black
holes could have formed shortly after the big bang.

(a) Stellar-Mass Black Hole
NASA/CXC/M.Weiss. Reproduced by
permission of NASA/CXC/M.Weiss.
Permission to reuse must be obtained
from the rightsholder.
(b) Supermassive Black Hole
NASA/CfA/HSCfA. Reproduced by
permission of NASA/CfA/HSCfA.
Permission to reuse must be obtained
from the rightsholder.
(c) Miniature Black Hole
NASA/JPL-caltech. Reproduced by
permission of NASA/JPL-caltech.
Permission to reuse must be obtained
from the rightsholder.

FIGURE 3 Different types of black holes, based on the mass.

 SBO for Biclustering Gene Expression Data 361

Formation and Evolution of a Stellar-Mass Black Hole

Stellar-mass black holes are born with a bang or when a massive star col-
lapses. When massive stars are collapsed, black holes of up to 103 solar masses
are produced. They form because of a massive star that runs out of nuclear
fuel and explodes as a supernova. The rest of the substance is a black hole
because the explosion blows much of the stellar material away (Chaisson and
McMillan 2008). A single stellar-mass black hole can grow quickly by consum-
ing nearby stars and gas, often in plentiful supply near the galaxy center. The
black hole might also merge with other black holes that drift to the galactic
center during collisions with other galaxies. The black holes actually evapo-
rate, slowly returning their energy to the universe. While emitting particles,
the black hole loses energy and it becomes smaller. Smaller black holes yield
more intense radiation than larger ones. The emission continues until the
death of the black hole.

Methodology
Based on the Stephen Hawking emission and absorption process, when
the black hole absorbs matter, the mass of the black hole is increased; during
emission its mass is reduced. Stellar-mass black holes can grow by pulling gas
of a companion star that orbits around it. The diet of known black holes con-
sists mostly of gas and dust, which fill the otherwise empty space throughout
the universe. Black holes can also consume material torn from nearby stars.
In fact, the most massive black holes can swallow stars whole. They can also
grow by colliding and merging with other black holes. A black hole gathers
any mass, then it grows in mass and slightly in size. The mass decreases via
a complicated process called black hole evaporation, or Hawking Radiation,
named for Stephen Hawking. Hawking radiation is black body radiation that
is predicted to be released by black holes due to quantum effects near the
event horizon.
The stellar-mass black hole has the following properties:

The mass of a black hole grows when it absorbs matter.

A black hole also grows by colliding and merging with other black holes.
When emitting particles a black hole loses energy and its mass is reduced.
Smaller black holes radiate more than larger ones.
The emission becomes more and more and the black hole is no more.

Based on the above properties, a new optimization technique is devised

that incorporates both diversification and intensification in the search space.
The individuals succeed to new characteristics that help them survive.
The optimization resembles an evolutionary technique, referring to the
362 R. Balamurugan et al.

TABLE 1 Comparison of Black Hole Socially Relevant Strategies with Optimization

Social Strategy SBO

Black hole Feasible solution to the problem

Black hole mass Fitness value
Black holes in the universe Population of feasible solution
Emission and absorption of a black hole Stochastic operators
Progression of populations to suit the universe Iteratively applying stochastic operators on a set
of feasible solutions

cumulative changes that occur in a population over time. Table 1 shows the
comparison of social strategies with SBO.
The perpetual mystery of the black holes is that they appear to exist
on radically different mass scales. There are the countless black holes that
are left over from massive stars. These stellar-mass black holes are peppered
throughout the Universe and are generally 10 to 24 times as massive as the
sun. Scientists estimate that there are as many as ten million to a billion
such black holes in the Milky Way alone. For the optimization problem, the
initial population of black holes with m dimensions is considered as a can-
didate solution for the problem. Each black hole is assigned a fitness value
according to the solution of the problem.

Evolution
The distance from the surface (or event horizon) of the black hole to
the center (or singularity) is called the Schwarzschild radius. This radius is
the size that any object would be if compressed enough to form a black hole;
it varies from only centimeters across to several kilometers across (Chaisson
and McMillan 2008). The Schwarzschild radius increases when the mass of
the original object increases but the actual radius does not. It is interesting
to mention that the irreducible mass is related to the area A of the event
horizon as shown below:

A
M = .
16

One way to grow a more massive black hole is for a seed black hole in
a dense galactic nucleus to swallow up gas and normal stars. It keeps on
growing by absorbing mass from its surroundings. By absorbing other stars
and merging with other black holes, supermassive black holes of millions of
solar masses may form. If two black holes merge together, then their event
horizons are contiguous. Figure 4 shows a growth of black hole and collision
of two black holes (Luminet 1998).
 SBO for Biclustering Gene Expression Data 363

FIGURE 4 Growth of a black hole.

The growth rate of a black hole is directly proportional to its mass.

The higher mass black hole has a higher absorption level, which is given
in Equation (4):

fi
i = . (4)

N
fi
i =I

fi : The fitness value of black hole i in the population 1 i N

N : The number of black holes in the population.

The most peculiar behavior that a black hole possesses is its ability to
radiate energy and through this process lose mass in the previously men-
tioned Hawking radiation process (Hamilton 1998). Hawkings radiation
theory of black holes also finds that the energy lost from a black hole is
inversely proportional to its mass. Larger mass black holes have low tem-
peratures and, therefore, dont radiate much energy. They also radiate at
low frequencies (e.g., radio or microwave frequencies). Smaller mass black
holes emit more energy; hence, they have higher temperatures and higher
frequency for their energy emission. Finally, the subsequent implication of
the inverse thermal/mass relationship is that a black hole will suffer from
thermal radiation runaway effects as its mass gets smaller toward the end of
its life, meaning that it will lose mass faster, the smaller it becomes. The black
hole with the lowest mass has the highest radiation. The radiation level i of
an individual black hole is given in Equation (5):
364 R. Balamurugan et al.

i = 1 i (5)

The mass of the black hole is changed based on the absorption and emis-
sion level. The mass of the black hole is updated using the following
Equation (6):

bi,d (t + 1) = bi,d (t) + ai,d (t) ei,d (t) (6)

bi,d : Value of ith black hole in dth dimension

ai,d : Absorption at dimension d in ith black hole
ei,d : Emission at dimension d in ith black hole
t: Time epoch

A spinning black hole drags space around with it and allows matter to
orbit closer to it. By measuring the spin of distant black holes, researchers
discover important clues about how these objects grow over time. If black
holes grow mainly from collisions and mergers between galaxies, they should
accumulate material in a stable disk, and the steady supply of new mate-
rial from the disk should lead to rapidly spinning black holes. In contrast,
if black holes grow through many small accretion episodes, they will accu-
mulate material from random directions. Stellar-mass black holes can grow
by pulling gas of a companion star that orbits around it. Based on the
characteristics, the growth of ith black hole in dth dimension is given in
Equation (7):
 
i bi,d (t) + i+1 bi+1 ,d (t)  i=1
ai,d = i1 bi1, d (t) + i bi,d (t) + i+1 bi+1, d (t) 1< i < N

i1 bi1 ,d (t) + i bi,d (t) i =N
(7)

Smaller black holes have more powerful radiation than larger ones. The
emissivity of a black hole is measured by the proportion of the actual emitted
radiance from a black hole, which is given in Equation (8):

ei,d = i bi,d , (8)

where 0 1 and i is the radiation level of the ith black hole.

Death of a Black Hole

Hawking radiation allows black holes to send away their energy, or mass.
It is generally accepted that if black holes radiate more mass than they
take in, they will eventually evaporate. Hamilton (1998) also says that many
large black holes have the potential to outlive the universe. The process
 SBO for Biclustering Gene Expression Data 365

for evaporation is simple: the black hole radiates, which causes the mass
to decrease; as the mass decreases, radiation increases; as the radiation
increases, the black hole evaporates more quickly and finally the black hole
is no more (Gottesman 1997). The black holes with very poor fitness value
will be removed from the population.

Collision of Black Holes

Scientists believe that the interaction of two black holes could have one
of two outcomes. The first is that they merge together to form one much
more massive black hole. The second is that because of spin, the two black
holes could interact and back away from each other, sending one dashing
away. The most possible scenario for two black holes is a merger. The total
mass would be the combined mass of the two black holes. If the two black
holes bp and bq are very close, then the they merge together and form the
new black hole bk using Equation (9):

bkd = rand() (bpd + bqd ) (9)

Pseudocode for Stellar-Mass Black Hole Optimization

Initialize a population of N candidate solutions Bk

While not (termination criterion)
For each Bk find fitness fk , growth level k and radiation level
k
For each Bk , update the mass using Equation (6)
Rank the solutions
Replace fraction of worst black holes with new black holes
Collide the nearest black holes and generate black holes for
left outs in the population
Keep the best solution
Next generation

Discussion of SBO Algorithm

The population size N is a tuning parameter. The optimization per-
formance of SBO will suffer when N is too small or too large. In typical
implementations of SBO, the value of N is somewhere between 20 and 200.
The initial population of candidate solutions Bk is usually randomly gen-
erated. The termination criterion is problem dependent, as in any other
evolutionary algorithm. In most applications, the termination criterion is a
generation count limit or a function evaluation limit. Smaller mass black
holes emit more energy, finally, at end of their lives. So the black holes with
366 R. Balamurugan et al.

lowest fitness values will be replaced by new black holes. It causes diver-
sity in the solution. If the two black holes are close, then the merging of
the black holes forms a new black hole, avoiding premature convergence.
The population size is fixed. So the new black holes are generated for those
left out.

Biclustering Representation
Each bicluster is encoded as a black hole in the universe. Size m + n
is the fixed length of every black hole, where m and n are the number of
genes and conditions of the microarray dataset, respectively. The first m bits
represent m genes and the following n bits represent n conditions. Each
bicluster is represented by a fixed-sized binary string called a black hole, with
a bit string of genes attached to another bit string for conditions. The black
hole represents a candidate solution for the optimal bicluster generation
problem. A bit is set to one if the corresponding gene and/or condition
is present in the bicluster, otherwise it is reset to zero. Figure 5 shows an
encoded representation of a bicluster.
The SBO works well for continuous optimization problems, so the indi-
vidual dimension of a black hole is represented by a real number. For binary
SBO, the following sigmoid function (Tasgetiren and Liang 2007) is used to
scale the velocities between 0 and 1, which is then used for converting them
to the binary values. That is,
1
sigmoid(bid ) = . (10)
1 + e bid
Figure 6 depicts the representation of the black hole and its mapping
to a bicluster. The new position of the particle is updated based on
Equation (11):

FIGURE 5 Encoding representation of a bicluster.

FIGURE 6 Representation of the black hole and its mapping to a bicluster.

 SBO for Biclustering Gene Expression Data 367


1, if U (0, 1) < sigmoid(bid )
bid = . (11)
0, otherwise

Fitness Function
Biclusters with coherent values are biologically more relevant than
biclusters with constant values. Hence, in this work, biclusters with coher-
ent values are identified. In order to identify the degree of coherence,
MSR score or Hscore is used. The MSR problem is proposed by Cheng
and Church (2000) for identifying biclusters. Let the gene expression data
matrix A have M rows and N columns where a cell aij is a real value that
represents the expression level of gene i under the condition j. Matrix A is
defined by its set of rows, R = {r 1 , r 2 , . . . , rM } and its set of columns C =
{c 1 , c 2 , . . . , cN }. Given a matrix, biclustering finds submatrices that are sub-
groups of genes and subgroups of conditions, where the genes exhibit highly
correlated behavior for every condition. Given a data matrix A, the goal is
to find a set of biclusters such that each bicluster exhibits some similar char-
acteristics. Let AIJ = (I, J ) represent a submatrix of A where I R and J
C. AIJ contains only the elements aij belonging to the submatrix with a set of
rows I and a set of columns J . The concept of bicluster was introduced by
Cheng and Church (2000) to find correlated subsets of genes and a subset
of conditions.
Let aiJ denote the mean of the ith row of the bicluster (I, J ), aIj the
mean of the jth column of (I, J ), and aIJ the mean of all the elements in the
bicluster. As given more formally,
  1 
a I, j =   ai,j
J 
jJ

  1 
a i, J = ai,j
|I |
iI

  1 
a I, J =   ai,j
|I | J  iI jJ

The residue of an element aij in a submatrix AIJ equals

 
r ai, j = ai, j + aI , J aI , j ai, J .

The difference between the actual value of aij and its expected value
predicted from its row, column, and bicluster mean are given by the residue
of an element. It also reveals its degree of coherence with the other entries
368 R. Balamurugan et al.

of the bicluster it belongs to. The quality of a bicluster can be evaluated

by computing the MSR H, i.e., the sum of all the squared residues of its
elements is given in Equation (12):
  1 
H I ,J =     r (ai,j )2 (12)
I  J 
iI jJ

The lowest score of H (I,J ) is 0, which indicates that the gene expres-
sion levels vary in harmony. This includes the trivial or constant biclusters
where there is no variation. These trivial biclusters might not be fascinat-
ing but need to be discovered and masked so more interesting ones can be
found. The gene variance may be a complementary score to discard trivial
biclusters. The gene variance can be represented in Equation (13) as follows:
  1 
Varr I , J = vr (i)
|I |
iI
(13)
1  2
r (i) =   ai, j ai, J .
J 
jJ

The optimization task is to find one or more biclusters by maintain-

ing the two competing constraints, viz., homogeneity and gene variance.
The fitness function for obtaining a bicluster is defined in Equation (14)
as follows:
1
f (I , J ) = H (I , J ) + (14)
Var(I ,J )

to be minimized. In this way, the smaller the residue and the larger the gene
variance are, the smaller the fitness value, in other words, the better the
quality of that bicluster is. The final objective of the SBO algorithm is to
minimize the fitness.

Identifying the Overlapping between the Biclusters

The microarray gene expression data may consist of a number of
biclusters. The best solution of each black hole is taken as a solution for a
bicluster. The most important part of the bicluster validation is the compar-
ison of a current bicluster to a well-known bicluster, which is found earlier.
The proposed work adapts the Jaccard index (Jaccard 1912) from identifying
similarity/overlapping between biclusters. Figure 7 illustrates the intersec-
tion and union of two biclusters. To compare the biclusters, it calculates the
fraction of row-column combinations in both (intersection) biclusters with
 SBO for Biclustering Gene Expression Data 369

FIGURE 7 Intersection and union of given two biclusters BCi and BCj .

respect to row-column combination in at least one (union) bicluster. The

Jaccard coefficient range is 01. Here, its threshold is 0.5. If the overlapping
rate is more than the threshold, the corresponding bicluster is removed. The
Jaccard index for two biclusters is given in Equation (15).
 
  BCi BCj 
jac BCi , BCj = jacij =  , (15)
BCi BCj 

where

BCi : ith bicluster

BCj : jth bicluster
|BCi BCj |: The size of intersection of two biclusters BCi and BCj
|BCi BCj |: The size of union of two biclusters BCi and BCj

Figure 8 depicts an example for checking the overlapping between the

set of biclusters from BC1 to BC4 arranged in ascending order of the fit-
ness value. The shaded portions show the overlapping rate to be identified
between the biclusters using the Jaccard index. The maximum Jaccard index
is considered as the overlapping rate of the bicluster. In general, mr (i) = max
(jacij ), where 1 j < i.
370 R. Balamurugan et al.

FIGURE 8 Finding the overlapping between the biclusters from BC1 to BC4 .

Pseudocode for Identifying Overlapping between the Biclusters

for each solution i from to 2 to n 1
Find the Jaccard index with previous (i 1) solutions
Get the maximum rate (mr )
If mr exceeds the given threshold
Reject the solution i
Otherwise
Present the solution i
End

EXPERIMENTAL RESULTS AND ANALYSIS

Benchmark Optimization Test Functions
Table 2 shows the 10 benchmark functions that are widely used for test-
ing the successes of SBO with PSO and CK (Civicioglu and Besdok 2011).
The dimensions of the benchmark functions vary between 2 and 30. The
global minimum values of each of the benchmark functions are obtained
by using a different initial population at every turn of 20 epochs. The pop-
ulation size is 50. The stopping criterion is up to the maximum iteration
2,000,000 or when the optimal check is reached. The best solution values,
mean-value of the global optimum values, standard deviation value of the
mean optimum values, and the mean iteration values of the function eval-
uation are computed by analyzing the global minimum values recorded
during the experiments, as shown in Tables 36, respectively. It is observed
from results that the proposed SBO algorithm outperforms the PSO and CK
when its dimensionality is large for the benchmark optimization functions.
This shows that increasing the dimensionality of the problem needs a better
algorithm such as SBO. The results show that the best optimum of SBO is
better than CK and PSO.
 TABLE 2 Benchmark Functions Used in Experiments

No. Function Min. Range D C Formulation

n 
F1 Rastrigin 0 [5.12,5.12] 30 MS f(x) = i=1 xi2 10 cos(2 xi ) + 10
  
2 2 2
F2 Rosenbrock 0 [30,30] 30 UN f(x) = n1
i=1 100(xi+1 xi ) + (xi 1)
 
sin2 x12 +x22 0.5
F3 Schaffer 0 [100,100] 2 MN f(x) = 0.5 +  2
1+0.001(x12 +x22 )
   
5 5
F4 Shubert 186.731 [10,10] 2 MN f(x) = i=1 i cos ((i + 1)x1 + i) i=1 i cos ((i + 1)x2 + i)
n 2
F5 Sphere 0 [100,100] 30 US f(x) = i=1 xi
n
F6 Step 0 [100,100] 30 US f(x) = i=1 ( xi + 0.5
)2
n
F7 Sum squares 0 [10,10] 30 US f(x) = i=1 ixi2
n 2 n
F8 Trid 50 [D2 ,D2 ] 6 UN f(x) = i=n (xi 1) i=2 xi xi 1
n
F9 Quartic 0 [1.28,1.28] 30 US f(x) = ix
i=1 i
4 + random 0, 1)
(
n 2
n 2 n 4
F10 Zakharov 0 [5,10] 10 UN f(x) = i=1 xi + i=1 0.5ixi + i=1 0.5ixi

Min: Global Minimum, D: Dimension, C: Characteristics, U: Unimodal, M: Multimodal, S: Separable, N: Nonseparable.

371
372 R. Balamurugan et al.

TABLE 3 Best Optimum Values of the SBO, CK, and PSO

No. SBO CK PSO

F1 0.0000000000000000 0.0003806178377204 13.9294167236679410

F2 0.0000000000000000 0.0000000000000000 0.0000700595196601
F3 0.0000000000000000 0.0000000000000000 0.0000000000000000
F4 186.7309091409600210 186.7309088310239800 186.7309088310239800
F5 0.0000000000000000 0.0000000000000000 0.0000000000000000
F6 0.0000000000000000 0.0000000000000000 0.0000000000000000
F7 0.0000000000000000 0.0000000000000000 0.0000000000000000
F8 50.0338354523580000 50.0000000000002270 50.0000000000001710
F9 0.0000000028478791 0.0013909553459754 0.0022391455486327
F10 0.0000000000000000 0.0000000000000000 0.0000000000000000

The bold font values represent the optimum values achieved by the algorithms.

TABLE 4 Mean Optimum Values of the SBO, CK, and PSO

No. SBO CK PSO

F1 0.0000000000000000 1.2828840539586595 28.0080704889407630

F2 0.0000000000000000 0.0000000000000000 2.3638709258458954
F3 0.0000000000000000 0.0000000000000000 0.0000000000000000
F4 186.7309890708511175 186.7309088310239800 186.7309088235984100
F5 0.0000000000000000 0.0000000000000000 0.0000000000000000
F6 0.0000000000000000 0.0000000000000000 0.0000000000000000
F7 0.0000000000000000 0.0000000000000000 0.0000000000000000
F8 50.5487614657409665 50.0000000000001920 50.0000000000001920
F9 0.0122237014923000 0.0021879618606472 0.0047745343217586
F10 0.0000000000000000 0.0000000000000000 0.0000000000000000

The bold font values represent the optimum values achieved by the algorithms.

TABLE 5 Standard Deviation (Mean) Optimum Values of the SBO, CK, and PSO

No. SBO CK PSO

F1 0.0000000000000000 1.0406975037000643 7.8693037959886158

F2 0.0000000000000000 0.0005667706273508 0.0018352361800625
F3 0.0000000000000000 0.0000000000000000 0.0000000000000000
F4 0.0000000000000021 0.0000000000000000 0.0000000332053694
F5 0.0000000000000000 0.0000000000000000 0.0000000000000000
F6 0.0000000000000000 0.0000000000000000 0.0000000000000000
F7 0.0000000000000000 0.0000000000000000 0.0000000000000000
F8 0.0000000002911607 0.0000000000000237 0.0000000000000219
F9 0.0000111765635760 0.0005667706273508 0.0018352361800625
F10 0.0000000000000000 0.0000000000000000 0.0000000000000000

The bold font values represent the optimum values achieved by the algorithms.

The setting values of algorithmic control parameters of the mentioned

algorithms are given below:
 SBO for Biclustering Gene Expression Data 373

TABLE 6 Mean Iteration of the Function Evaluation Values of the SBO, CK, and PSO

No. SBO CK PSO

F1 899.95 1,993,640.00 712,470.00

F2 28.95 1,497,570.00 1,999,950.00
F3 1,036,268.00 260,375.00 246,82.50
F4 26.70 955,790.00 640,845.00
F5 1,114,737.00 408,885.00 205,107.50
F6 2,000.00 88,350.00 56,950.00
F7 235.15 393,375.00 197,022.50
F8 544.05 228,320.00 170,175.00
F9 2,857.30 1,713,795.00 1,882,150.00
F10 538.70 221,570.00 123,570.00

The bold font values represent the optimum values achieved by the algorithms.

CK Settings: = 1.50 and pa = 0.25 have been used as recommended in

Yang and Deb (2009).
PSO Settings: c 1 = c2 = 1.80 and = 0.60 have been used as recommended
in Karaboga and Akay (2009).
SBO settings: In our experiments, absorption rate = 0.5 and emission rate
= 0.9 was employed.

Datasets
The proposed algorithms for the bicluster problems are coded in
MATLAB and run on an Intel i3 3.7 GHz. The biclustering algorithm
has been applied to four well-known datasets in order to study its per-
formance: the yeast Saccharomyces cerevisiae stress expression data (Gasch
et al. 2000), Arabidopsis thaliana expression data (Bleuler, Prelic, and Zitzler
2004), yeast Saccharomyces cerevisiae cell cycle expression data (Cho et al.
1998), and rat CNS expression data (Wen et al. 1998). The first Gasch
yeast is the Saccharomyces cerevisiae with 2993 genes and 173 conditions.
The second one, Arabidopsis thaliana expression data, contain 734 genes
and 69 conditions. The third dataset, yeast Saccharomyces cerevisiae cell cycle
expression, contains 2884 genes and 17 experimental conditions. The rat
CNS dataset has a set of 112 genes under 9 conditions. Through empir-
ical analysis, the population size and the number of iterations are set
as 20 and 200 respectively. Figures 912 show the fitness value obtained
for Saccharomyces cerevisiae expression data, Arabidopsis thaliana expression
data, yeast Saccharomyces cerevisiae cell cycle expression data, and rat CNS
expression data, respectively. The PSO has premature convergence due to
stagnation. For all the datasets, the proposed SBO outperforms the PSO and
CK algorithms because intensification and diversification is involved with the
SBO algorithm.
374 R. Balamurugan et al.

FIGURE 9 Plot of number of iterations versus fitness value for yeast stress data.

FIGURE 10 Plot of number of iterations versus fitness value for Arabidopsis thaliana data.

According to the problem formulation, the size of an extracted bicluster

should be as large as possible while satisfying a homogeneity criterion.
The bicluster should satisfy two requirements simultaneously. The expres-
sion levels of each gene within the bicluster should be similar over the
range of conditions. That is, it should have a low MSR score. However, the
bicluster gene variance should be high. The MSR represents the variance of
the selected genes and conditions with respect to the homogeneity of the
bicluster, and gene variance removes the simple (trivial) bicluster. In order
to quantify the biclusters homogeneity and size, the Coherence Index (CI)
is used as a measure for evaluating their goodness. CI is defined as the ratio
 SBO for Biclustering Gene Expression Data 375

FIGURE 11 Plot of number of iterations versus fitness value for yeast cell cycle data.

FIGURE 12 Plot of number of iterations versus fitness value for rat CNS data.

of MSR score to the size of the formed bicluster. Tables 710 show sample
experimental results obtained for Saccharomyces cerevisiae expression data,
Arabidopsis thaliana expression data, yeast Saccharomyces cerevisiae cell cycle
expression data, and rat CNS expression data, respectively, and the biclusters
are chosen randomly from 20 biclusters. Clearly, Figure 13 shows a sample
bicluster of size 10 5 for Arabidopsis thaliana data.

BIOLOGICAL ANALYSIS OF BICLUSTERS

Once high-level analysis methods have recommended some underlying
structure in the data, then the results need to be interpreted and validated
376 R. Balamurugan et al.

TABLE 7 Experiment Results for Saccharomyces cerevisiae Stress Expression Data

Bicluster No. Genes Samples Volume MSR Gene Variance CI Fitness

BC1 1500 86 129000 0.6853 0.7049 5.3 106 2.1039

BC3 1531 66 101046 0.7054 0.7226 6.9 1106 2.0892
BC7 1484 77 114268 0.7274 0.7505 6.4 106 2.0598
BC10 1490 79 117710 0.6743 0.6914 5.7 106 2.1206
BC15 1482 80 118560 0.6561 0.6773 5.5 106 2.1325

TABLE 8 Experiment Results for Arabidopsis thaliana Expression Data

Bicluster No. Genes Samples Volume MSR Gene Variance CI Fitness

BC1 366 26 9516 926.65 929.15 0.0973 926.65

BC2 353 29 10237 867.40 870.45 0.0847 867.40
BC6 364 25 9100 948.93 951.72 0.1042 948.93
BC9 377 32 12064 974.26 976.88 0.0807 974.26
BC17 347 35 12145 854.75 857.08 0.0703 854.76

TABLE 9 Experiment Results for Saccharomyces cerevisiae Cell Expression Data

Bicluster No. Genes Samples Volume MSR Gene Variance CI Fitness

BC1 1422 3 4266 429.11 453.67 0.1005 429.12

BC3 1441 4 5764 464.19 499.22 0.0805 464.19
BC5 1440 2 2884 395.66 436.98 0.0934 395.66
BC7 1503 3 4509 534.79 553.01 0.1186 534.79
BC9 1404 6 8424 572.45 605.87 0.0679 572.46

TABLE 10 Experiment Results for Rat CNS Expression Data

Bicluster No. Genes Samples Volume MSR Gene Variance CI Fitness

BC1 55 2 110 0.6169 0.9084 0.0056 1.7177

BC4 57 3 171 0.8038 1.0443 0.0047 1.7615
BC8 49 2 98 0.8797 1.1528 0.0089 1.7472
BC10 54 5 270 0.7881 1.0536 0.0029 1.7372
BC13 50 4 200 0.9190 1.2242 0.0045 1.7359

in terms of biological significance. The proposed work determines the bio-

logical relevance of the biclusters found by SBO on the Gasch yeast dataset
in terms of the statistically significant Gene Ontology (GO) Annotation
Database. In this database, the gene products are described in terms of
associated biological process, components, and molecular functions in a
species-independent manner. The degree of enrichment is measured by p-
values, which use a cumulative hypergeometric distribution to compute the
probability of observing the number of genes from a particular GO category
(function, process, and component) within each bicluster. A bicluster is said
 SBO for Biclustering Gene Expression Data 377

FIGURE 13 Plot of sample biclusters of size 10 5 for Arabidopsis thaliana expression data.

to be over represented in a functional category if the p-value is below a cer-

tain threshold. The probability p for finding at least k genes from a particular
category within a bicluster B of size m is given in Equation (16).
G  M G 

k1
p(B) = 1 r
 mr
 , (16)
M
r =0 m

where G and r are the number of genes associated with the given category in
the gene expression matrix and in the bicluster, respectively, while M and m
are the number of genes in the gene expression matrix and in the biclusters,
respectively. The p-value is the probability that the genes are selected into
the cluster by random. If the p-value is smaller, then the match will be better.
The annotations of genes for three ontologies including biological process,
cellular component, and molecular function are obtained.

Biological Annotation for Yeast Stress Data Using GOTermFinder

Toolbox
In order to identify the biological annotations for the biclusters, we use
GOTermFinder,1 which is a tool available in the Saccharomyces Genome
Database. GOTermFinder is designed to search for the significant shared
GO terms of the groups of genes and provides users with the means to

1 GOTermFinder for yeast stress data, http://www.yeastgenome.org/cgi-bin/GO/goTermFinder.pl.

378 R. Balamurugan et al.

TABLE 11 Significant GO Terms for Three Biclusters on Yeast Stress Data

Bicluster No. of
No. Genes Process Function Component

BC1 1500 Cellular process DNA binding activity Intracellular part

(n = 1386, p = 2.3810144 ) (n = 490, p = 7.82108 ) (n = 1370, p = 2.901083 )
BC3 1531 Single-organism process Hydrolase activity Cell part
(n = 10836, p = 8.351091 ) (n = 290, p = 2.061016 ) (n = 1455, p = 1.0710125 )
BC7 1484 Metabolic process Protein binding Organelle
(n = 1155, p = 8.711098 ) (n = 227, p = 1.511020 ) (n = 1180, p = 1.511064 )

identify the characteristics that the genes might have in common. Table 11
lists the significant shared GO terms used to describe the set of genes in
each bicluster for the process, function, and component ontologies. Only
the most significant terms are shown. For example, to the bicluster BC1 ,
the genes are mainly involved in binding activity. The tuple (n = 490, p =
7.82 108 ) represents that out of 1500 genes in bicluster BC1 , 490 genes
belong to binding activity function, and the statistical significance is given by
the p-value of p = 7.82 108 . In Figure 14, the biological network of the
bicluster with 10 genes, it is clear that the false discovery rate (FDR) is very
low and it is zero on many occasions. Further, the corresponding p-value is
very small (p = 0.000562), which shows that there is a very low probability
to obtain the gene cluster in random. These results mean that the proposed
SBO biclustering approach can find biologically meaningful biclusters.

Functional Annotation for Arabidopsis thaliana Using DAVID

Toolbox
The Functional Annotation Tool of the Database for Annotation,
Visualization, and Integrated Discovery2 is used for the enrichment analysis
of the gene terms annotated for the input gene set. The basic prin-
ciple behind the enrichment analysis is that, if a biological process is
active/abnormal then the cofunctioning genes have a higher chance of
being selected as a relevant group. Table 12 lists the significant GO terms
used to describe the set of genes in each bicluster for biological activities. For
example, for bicluster BC1 in Arabidopsis thaliana data, the GO process (GO:
0044271) is involved mainly in the nitrogen compound biosynthetic pro-
cess. In this first row, 87 out of 366 genes belong to the nitrogen compound
biosynthetic process; the total enrichment score is 44.61 and the statistical
significance is given by the p-value of p = 9.51052. The lower the p-value
and the higher the gene enrichment value are, the more statically significant
the bicluster is.
2 http://david.abcc.ncifcrf.gov/summary.jsp.
 SBO for Biclustering Gene Expression Data 379

FIGURE 14 Gene ontology biological process of yeast stress data with 10 genes.

TABLE 12 Functional Annotation for Bicluster on Arabidopsis thaliana Data

Enrichment
GO Number Ontology Description Score Genes p-value

GO:0044271 Nitrogen compound biosynthetic 44.61 87 9.5 1052

GO:0016053 Organic acid biosynthetic 44.61 83 3.1 1055
GO:0009536 Plastid 33.92 141 1.7 1022
GO:0009507 Chloroplast 33.92 139 2.5 1022
GO:0005996 Monosaccharide metabolic 14.86 42 3.6 1029

CONCLUSIONS
In this work, a novel algorithm, stellar-mass black hole optimization
(SBO), is proposed for biclustering gene expression data. This optimization
algorithm is deduced from the properties of a stellar-mass black hole. It is a
380 R. Balamurugan et al.

nature-inspired, swarm-based, heuristic approach. Initially it starts with a ran-

dom population of black holes and it endures to find the optimum mass of
the universe. The mass of the black hole changes based on its absorption and
emission. New solutions are generated by adjusting absorption and emission
rates. When the mass of the black hole is small, it radiates more and finally
it ends. When two black holes are in close proximity, they collide with each
other. These properties are mimicked in the SBO algorithm to solve the opti-
mization problems. SBO uses only a few parameters for adjusting. It contains
both intensification and diversification during stagnation of the best solu-
tion. The results obtained from SBO are analyzed and compared with the
swarm intelligence techniques PSO and CK with ten widely used benchmark
optimization test functions and four benchmark gene expression datasets.
The experiment results show that the proposed SBO outperforms the swarm
intelligence techniques PSO and CK.

FUNDING
This work is supported by the research grant from Department of
Biotechnology (DBT), Government of India, New Delhi, Grant No. BT/
PR3741/BID/382/2011.

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