RESEARCH ARTICLE

A three-way approach for protein function

classification
Hafeez Ur Rehman1☯*, Nouman Azam1☯, JingTao Yao2☯, Alfredo Benso3☯
1 Department of Computer Science, National University of Computer and Emerging Sciences, Peshawar
Pakistan, 2 Department of Computer Science, University of Regina, Regina, SK S4S 0A2, Canada,
3 Department of Computer & Control Engineering, Politecnico di Torino, I-10129, Torino, Italy

☯ These authors contributed equally to this work.

* [email protected]
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a1111111111 Abstract
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The knowledge of protein functions plays an essential role in understanding biological cells
and has a significant impact on human life in areas such as personalized medicine, better
crops and improved therapeutic interventions. Due to expense and inherent difficulty of bio-
OPEN ACCESS
logical experiments, intelligent methods are generally relied upon for automatic assignment
of functions to proteins. The technological advancements in the field of biology are improv-
Citation: Ur Rehman H, Azam N, Yao J, Benso A
(2017) A three-way approach for protein function ing our understanding of biological processes and are regularly resulting in new features
classification. PLoS ONE 12(2): e0171702. and characteristics that better describe the role of proteins. It is inevitable to neglect and
doi:10.1371/journal.pone.0171702 overlook these anticipated features in designing more effective classification techniques. A
Editor: Yong Deng, Southwest University, CHINA key issue in this context, that is not being sufficiently addressed, is how to build effective
Received: August 1, 2016 classification models and approaches for protein function prediction by incorporating and
taking advantage from the ever evolving biological information. In this article, we propose a
Accepted: January 6, 2017
three-way decision making approach which provides provisions for seeking and incorporat-
Published: February 24, 2017
ing future information. We considered probabilistic rough sets based models such as Game-
Copyright: © 2017 Ur Rehman et al. This is an Theoretic Rough Sets (GTRS) and Information-Theoretic Rough Sets (ITRS) for inducing
open access article distributed under the terms of
three-way decisions. An architecture of protein functions classification with probabilistic
the Creative Commons Attribution License, which
permits unrestricted use, distribution, and rough sets based three-way decisions is proposed and explained. Experiments are carried
reproduction in any medium, provided the original out on Saccharomyces cerevisiae species dataset obtained from Uniprot database with the
author and source are credited. corresponding functional classes extracted from the Gene Ontology (GO) database. The
Data Availability Statement: All relevant data are results indicate that as the level of biological information increases, the number of deferred
within the paper and its Supporting Information cases are reduced while maintaining similar level of accuracy.
files.

Funding: The third author was partially supported

by Discovery Grant from NSERC Canada. We are
also thankful to the Higher Education Commission
of Pakistan for providing student grant under the
SRGP (Startup Research Grant Program) initiative. Introduction
There was no additional external funding received
for this study. The funders had no role in study All living organisms are composed of cells, which are intricately arranged chemical factories
design, data collection and analysis, decision to that obtain matter from their environment and use this raw matter to generate copies of them-
publish, or preparation of the manuscript. selves [1]. Behind this miraculous functioning of the cells are the most important biochemical
Competing interests: The authors have declared molecules called proteins. Due to their role in almost every biological activity, it is crucial to
that no competing interests exist. have a clear understanding of their respective functions. Moreover, the knowledge of protein

PLOS ONE | DOI:10.1371/journal.pone.0171702 February 24, 2017 1 / 29

 Protein function classification

functions is also essential for understanding how biological activities are performed at the
molecular level. This is useful in developing personalized medicine, more effective therapeutic
interventions as well as understanding biological entities as engineered systems [2–7]. On the
other hand, when the number of sequenced genomes are growing, the overwhelming majority
of new proteins with unknown functions continue to emerge at an exponential rate. Under
these conditions, it is not feasible to manually identify and assign functions to proteins. Intelli-
gent mechanisms are generally relied upon to automatically predict and assign functions to
proteins [8–10].
Several methods have been proposed for characterization of protein functions. The early
and conventional techniques were generally based on the most fundamental type of informa-
tion about proteins i.e., their amino acid sequence, utilizing tools such as Basic Local Align-
ment Search Tool (BLAST) [11]. Sequence of a protein determines its different characteristics
such as its sub-cellular localization, possible structural conformations as well as its functions
[3]. Some of the prominent approaches in this category can be found in [12–14]. With the
availability of data from massive high-throughput experiments, features based on different
data such as genomic contextual data and Protein-Protein Interactions (PPIs) data, has also
emerged. Recent and advanced computational methods utilized these and similar information
in designing approaches for prediction task. For example, features based on genomic contex-
tual data were utilized by [12, 15, 16], features based on protein-protein interaction data were
used by [17–20], and features exploiting function structure relationship were reported in [21–
23]. As we have access to more interesting information, we may expect more effective models
and approaches for precise prediction of protein functions.
Due to technological advancements, our understanding of biological processes is improving
and new features describing proteins are emerging on regular basis [3]. It is inevitable to
ignore these anticipated features in designing more effective and efficient prediction tech-
niques. An important issue that needs to be addressed in this context is how to develop effec-
tive models by incorporating and taking advantage from the ever evolving biological
information that leads to new features and characteristics of proteins. This however has gener-
ally been overlooked and received little or no attention in the existing literature. A general
assumption, although not explicitly stated, is that the information is being fixed (i.e., not
dynamic and evolving) while developing classification approaches. This assumption may not
be always useful, for instance, consider the classification of proteins whose functions may not
be precisely identified due to lack of associated biological information (although we may antic-
ipate it in future) thereby leading to compromised results. To address this issue, i.e., incorpo-
rating the anticipated future information into the predictive task, we propose a three-way
decision making approach that includes a decision option of deferment. This option is exer-
cised whenever we have inconclusive and insufficient evidence to reach confirmed or certain
decisions. The deferred decision option provides provisions for incorporating future informa-
tion which may be used in deciding the deferred cases. In particular, three types of decisions
are used, i.e., accept, reject and deferment in order to classify functions of proteins.
There are different models for inducing three-way decisions. In this article, we investigate
and examine probabilistic rough sets based three-way decision making approaches for protein
functions classification [24]. The probabilistic rough sets can be used to induce three regions
corresponding to a concept (represented in terms of a set), namely, positive, negative and
boundary regions. The three regions lead to three-way decisions in the form of acceptance,
rejection and deferment, respectively. The three regions and their respective decisions are
defined and controlled by a pair of thresholds. There are different forms and models of proba-
bilistic rough sets based on how these thresholds are obtained and interpreted. We consider
two such models, i.e., Game-Theoretic Rough Sets (GTRS) [25–27] and Information-Theoretic

PLOS ONE | DOI:10.1371/journal.pone.0171702 February 24, 2017 2 / 29

 Protein function classification

Rough Sets (ITRS) [28]. Moreover, we examine and define five three-way approaches based on
the GTRS and ITRS by employing different measures and iterative methods. To incorporate
and take benefit from these three-way approaches in real applications, we propose an architec-
ture of protein functions classification. Lastly, we evaluated the three-way approaches on the
dataset of Saccharomyces cerevisiae species proteins which is obtained from Uniprot database
[29], with the corresponding functional classes extracted from the well known Gene Ontology
(GO) database [30]. The experimental results indicate that by increasing the level of biological
information associated with proteins, the number of deferred cases can be reduced while
maintaining the same level of accuracy. We comprehensively benchmark our approaches
under these settings and conclude that the classification becomes more crisp as the knowledge
of associated biological information matures.
The code (Python/Bash/Matlab) and data files used in this work are available as a zip file
(“Protein_Functions_TWD_data_code.zip”) from http://tinyurl.com/jdpwkkq.

Background
Protein function classification
An important factor that impacts the performance of function prediction models is the type of
biological information used to infer functional association among proteins. Until recently,
many high throughput techniques have been developed to devise mechanisms leading to pre-
cise prediction of protein functions. These techniques utilize information derived from
sequence similarity, protein 3D structure, phylogenetic profiles, protein complexes, PPIs, gene
expression profiles [31–33]. The most prominent techniques utilize proteome-scale PPI net-
works that have been retrieved for several organisms including yeast and human. Protein-pro-
tein networks are graphs where each node represents a protein and edges between nodes
represent an interaction. An interaction in the network is either a direct physical association
between the proteins (typically retrieved via two hybrid analysis [34] or on the other hand if
two interacting proteins are part of the same multi-protein complex, they are also considered
as interacting proteins [35]. Thus from informatics point of view an interaction is not neces-
sarily a direct physical association of proteins but sometimes it is mutual presence in the same
protein complex depending on the experiment which reveals the interaction.
The most recent as well as renowned approaches in the field of protein function prediction
use protein-protein interactions data in different ways [31–33]. A wide majority of these tech-
niques are based on the fact that interacting proteins are likely to share common functions as
they interact for an associated biological activity. Methods in this category assign annotations
to protein under question, based on the functions of their neighboring proteins. The methods
vary in the extent to which they employ global features of the interactome in annotating pro-
teins, or the way they exploit the topological features of the interactome [17, 18]. In addition to
that, the methods are based on quite varied underlying formulations and use well understood
concepts from the fields of graph theory, graphical models, stochastic processes, probabilistic
graphs or clustering [18, 19].
Another class of approaches are based on utilizing the GO structure into computational
models by incorporating the semantic similarity offered by the Direct Acyclic Graph (DAG)
architecture of gene ontology. The integration of multi-level gene ontology terms exploiting
their relationships for protein function prediction was investigated in [2, 8, 9, 36]. These meth-
ods calculate different similarity measures by operating on GO term dependencies to define
functional associations among proteins. A similar technique based on the Markov Random
Field (MRF) properties of protein-protein networks, integrated the inter-species protein
homolog information to construct MRF based graphs using the gene ontology terms was

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 Protein function classification

outlined in [8]. The authors report high precision when tested for a limited set of functional
terms [8].
Another type of biological information that is frequently used for uncharacterized proteins
is the number of motifs conserved in those proteins [9, 36]. Several functionally conserved pro-
teins are found to have motifs that associate them to a particular molecular activity. For exam-
ple, hypothetical protein YIL169C is conserved with Chemotaxis_Transduce_2 and T_SNARE
motifs, and similar motifs in known proteins can be used to link functional information with
the protein under investigation. Integrating heterogeneous information conserved across pro-
teins of unknown function, with state of the art classification scheme may help to increase pro-
tein function prediction accuracy.
The existing computational approaches have significantly contributed in understanding
and characterizing protein functions by investigating and utilizing different types of features.
However, there is still a need for approaches to incorporate and integrate the ever evolving fea-
tures of proteins for precise prediction of their functions. These new features, once known and
available, will give better insight into biological activities thereby are expected to provide more
precise characterization of proteins. In the later sections of this article, we present a three-way
approach to address these issues.

Three-way decisions
In many real life decision making scenarios involving vague and uncertain information, the
three-way decision making strategy including a delay, deferment or non-commitment deci-
sion option is a better and more useful approach [37–39]. To explain this, consider the follow-
ing examples: 1) How do we make a purchase decision based on information gathered from
blogs, reviews, friend suggestions and experiences? 2) How do doctors make diagnosis deci-
sions based on the presence of some symptoms and tests? 3) How do military commanders
decide to carry out military actions based on intelligence information? In all these and similar
decision scenarios, the decision makers are faced with two types of situations. Either they have
sufficient and convincing information necessary to make a decision or they are faced with
vague and incomplete information which is insufficient to make a useful decision. In the for-
mer case, the decision makers can exercise immediate and certain decisions in the form of
acceptance/rejection, yes/no or true/false. In the latter case, the decision makers may not be
able to make certain decisions. For instance, the diagnosis tests are inconclusive or the intelli-
gence information is vague or incomplete. A better and more useful choice in such uncertain
and doubtful situations is to delay the decisions, assuming that future information will evolve
which will make the decision making more obvious and evident. Three-way decisions is essen-
tially the same approach to decision making. We make immediate accept or reject decisions if
we have convincing and sufficient evidence based on the available information. On the other
hand, we make a deferment decision whenever we lack sufficient evidence.
In fact, three-way decisions has been practiced over the years across different domains,
including, medical decision making, psychology, social judgment theory, management sci-
ences and machine learning [40–44]. These application domains suggest that three-way deci-
sions enjoy a good history from usage and application perspective, however, it is surprising to
note that from theoretical perspective, it lacks a unified formal description over the years [45].
This theoretical gap was first recognized in the rough sets community. In particular, Yao intro-
duced a general theory of three-way decisions, motivated by the rough sets based three regions
[45]. The essential notion in the theory adopted from rough sets is the division of the universe
into three pair-wise disjoint regions. The theory however is not restricted to rough sets and
goes beyond it by considering rough set theory as one of many possible ways to construct and

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 Protein function classification

induce the three regions [39, 46]. Three-way decisions may be formulated based on the theo-
ries such as rough sets, interval sets, shadowed sets, approximations of fuzzy sets, a threshold
approach in medical and orthopairs [47–54].
An important consideration in formulating three-way decisions is the division of the uni-
versal set into three pair-wise disjoint regions. It is recently argued that an equally important
consideration is the design of effective strategies for processing the three regions [39]. The real-
ization of these two essential components, i.e., division and processing lead to the trisecting
and acting framework of three-way decisions [39].
The trisecting and acting framework explains and presents three-way decisions as a two
step process. In the first step, i.e., trisecting, the universe is divided into three pair-wise disjoint
regions. This means that we seek tripartition of the universe. In the second step, i.e., acting,
strategies are designed for processing the three regions to obtain three-way decisions. This
framework aimed at introducing three-way decisions at a more generic level. Generally, the
division of the universe is carried out based on an evaluation function and a pair of thresholds.
The evaluation function assign an evaluation value to each object by employing some criteria.
The objects whose evaluation values are at or above a certain threshold of acceptance makes
up the POS region. The objects whose evaluation values are at or below a certain threshold of
rejection make up the NEG region. The objects whose evaluation values are above the rejection
threshold but below the acceptance threshold make up the BND region. A specific definition
of evaluation based three-way decisions based on a single evaluation function (used for evalu-
ating both acceptance and rejection) and totally order set is given in [39].
There are many issues and challenges for building and using three-way decision models.
Some of these issues include the definition and construction of evaluation functions, the defi-
nition of the domains for the evaluation functions, the determination and interpretation of
acceptance and rejection levels, the measurement of the quality of the three regions, generation
of predictive rules from the three regions for making decisions on new objects, descriptive
rules for describing the three regions and design of strategies and actions corresponding to the
three regions [39, 45]. Based on how these issues are handled and interpreted, we may have dif-
ferent three-way decision making models and approaches. We focus on three-way decisions
with probabilistic rough sets.

An architecture of protein function classification with three-way

decisions
To make effective use of three-way decisions, we propose an architecture for supporting pro-
tein functions classification decisions. The architecture may be utilized in building systems to
provide decision support capabilities for deciding protein functions. Fig 1 shows the logical
view of the architecture and highlights its intended applications. The architecture supports
user queries in the form of protein IDs (also called Uniprot IDs) which are mapped to func-
tional classes by making use of three-way decisions. Fig 2 shows the physical view of the archi-
tecture along-with its various components. These components have different capabilities and
functionalities ranging from supporting interaction of end user using interface to storing, col-
lecting and manipulating the data for providing decision support.
The clients or end users will interact with the system through interfaces. Considering a typi-
cal client-server model over the Internet platform where the system is deployed over the serv-
ers and provides services by responding to client queries. The interfaces may be presented to
the end users through Web browsers. The users can send their queries on proteins and see the
resulting functions returned by the system. The interfaces should be carefully designed and
has to be clear, complete, consistent and should provide guidance to users for correctly using

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 Protein function classification

Fig 1. Logical view of the architecture with three-way decisions for protein function classification.
doi:10.1371/journal.pone.0171702.g001

the systems. In some cases, it may also provide auto correction facility. Besides interface, there
are various other components at the core of the architecture namely Knowledge Discovery,
Feature Extractor, Learning Module, Knowledge Base and Control Functions. We now
explains each of them briefly with their intended functionalities.
Knowledge Discovery/Information Retrieval: The Knowledge Discovery module interacts
with both the worldwide biological databases and feature extractor module. As new features
are evolving, the feature extractor module may require different type of biological information
to compute feature values. On one hand, it will provide querying and searching facilities for
extracting information from relevant biological databases and on the other side, it is responsi-
ble for passing them to the feature extractor module.
Feature Extractor: The features describing proteins are computed based on relevant data
extracted from biological databases which are spread around the world. The feature extractor
module request or query the information retrieval component for providing relevant informa-
tion necessary for computing a feature value. The information retrieval component extracts
the required information from the world wide biological databases. For example, for getting
one of the features namely, protein interaction networks (PIN), this module will ask for rele-
vant information, i.e., number of interactors corresponding to a protein. The information
retrieval identifies and searches the relevant databases such as STRING and IntAct databases
and will pass the respective information to the feature extractor. The feature extractor module

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 Protein function classification

Fig 2. Physical view of the architecture with three-way decisions.

doi:10.1371/journal.pone.0171702.g002

is then responsible for further processing in order to calculate the feature value, e.g. the num-
ber of interactors present in both the databases. As new features become available due to tech-
nological advancements, the feature extractor module will ask for new type of information
from the information retrieval component and do the relevant computation and processing to
calculate feature values. In section Data Preparation, we describe different types of features
that have evolved over the time and explain the types of data that is required to computed
them.
Learning Module: The learning module interacts with the feature extractor and knowledge
base. This module will incorporate intelligent techniques to make useful inferences from the
data to reach effective classification decisions. In this article, we suggest a classification mecha-
nism based on three-way decisions as one of the possibility. An important output of the learn-
ing module will be a set of functions that are being performed by a protein.
Knowledge Base: The knowledge base contains necessary information that is learned and
made available by the learning module. The information, such as, decision thresholds and
rules for classifying proteins may be stored in the knowledge base for future use.
Control Functions: This module is included to ensure security and protect the system from
attacks and unauthorized usage. It should provide functionalities such as access rights and
permissions.

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 Protein function classification

Realization of rough sets based three-way decisions

Three-way decisions is a better and useful choice in applications with evolving information. In
this section, we explain this phenomena using rough sets based three-way decisions. For the
sake of completion, we review the main notions of rough sets.

Three-way decisions using rough sets

Three-way decisions using rough sets are defined by considering an information table S which
is defined as a tuple.
S ¼ ðU; At; fVa ja 2 Atg; fIa ja 2 AtgÞ; ð1Þ

where U is a finite set of objects also known as the universe, At is a finite set of attributes, Va is
the domain of attribute a 2 At and Ia is an information function which provides a mapping
from U ! Va. In particular, the information function Ia assigns to each object x 2 U a value in
Va i.e., Ia(x) 2 Va. A major concern in rough set theory is how to discern objects. The equiva-
lence relation defined on U is used for this purpose. For a set of attributes A  At, the equiva-
lence relation, namely, EA is defined as,
EA ¼ fðx; yÞ 2 U  Uj8a 2 A; Ia ðxÞ ¼ Ia ðyÞg: ð2Þ

This means that any two objects x and y in U are equivalent or in other words indiscernible
based on attribute set A 2 At if they share the same values on all attributes in A.
The equivalence relation may be used to create equivalence classes which induces a parti-
tion of U denoted by U/E. An equivalence class with an object x is given by [x] = {y 2 U|xEy}.
The fundamental notion of rough set theory, i.e., approximations and the three regions are
defined using equivalence classes as follows.
aprðCÞ ¼ fx 2 U j ½xŠ  Cg; ð3Þ

aprðCÞ ¼ fx 2 U j ½xŠ \ C 6¼ g: ð4Þ

The lower and upper approximations are used to define the positive, negative and boundary
regions (which leads to three-way decisions, already discussed in the section Three-way Deci-
sions) given by [24, 55],
POSðCÞ ¼ aprðCÞ
ð5Þ
¼ fx 2 U j ½xŠ  Cg;

c
NEGðCÞ ¼ ðaprðCÞÞ
ð6Þ
¼ fx 2 U j ½xŠ \ C ¼ g;

BNDðCÞ ¼ aprðCÞ aprðCÞ

ð7Þ
¼ fx 2 U j ½xŠ⊈C; ½xŠ \ C 6¼ g:

The three regions has a simple but very meaningful interpretation. We accept an object as
belonging to the concept if it is in the positive region. We reject an object as belonging to the
concept if it is in the negative region. We defer the decision for an object as belonging to the
concept if it is in the boundary region. The three regions representation of rough sets defined
in Eqs (5)–(7) has lead to the introduction of the theory of three-way decisions [39]. In fact,

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 Protein function classification

Table 1. An information table for proteins.

Objects Localization available at t0 Interacting proteins available at t1 No. of Domains available at t2 Function
P1 Mitochondria 0 0 Yes
P2 Mitochondria 0 1 No
P3 CytoPlasm 1 0 Yes
P4 CytoPlasm 2 0 No
P5 CytoPlasm 2 0 No
P6 CytoPlasm 0 0 Yes
P7 CytoPlasm 2 1 No
P8 Mitochondria 0 1 No
doi:10.1371/journal.pone.0171702.t001

the major notion of three-way decisions, i.e., the division of universal set into three regions is
borrowed from rough sets.
The deferment decision option which is exercised based on the boundary region is useful in
at least two aspects. Firstly, it provides hints for seeking and incorporating anticipated future
information in the decision making model for making decisions on the deferred cases. It is
hoped that as information matures, the number of deferred cases will reduce thereby leading
to more precise decisions. Secondly, the deferred cases which are typically associated with high
levels of uncertainty and therefore, no obvious immediate decisions, the deferment decision
option may help avoiding some false decisions. The former aspect is of particular interest from
protein functions classification perspective We further elaborate this in the next section.

Three-way decisions and evolving information

The information describing the functions of proteins are evolving. An interesting issue is how
to build effective decision making model for taking advantage of evolving information of pro-
tein functions. In this section, we elaborate the role of rough sets based three-way decisions as
one of the possibility. In particular, we explain, how evolving information leading to new fea-
tures can be effectively utilized in three-way decision making based on rough sets. We consider
a demonstrative example for this purpose based on an information table of Table 1.
The rows of the Table 1 represent the proteins labeled as Pi’s and the columns describe the
feature or characteristics of proteins. The last column labeled as “Function” represents the
decision attribute. The Function = Yes means that a protein performs the function and
Function = No means that the protein does not perform the function. Let us assume three
instances in time, i.e., t0, t1 and t2 with t0 < t1 < t2. Further assume that at time instance t0, we
only have information about the “Localization” of the proteins. At time instance t1, we have
additional information of “interacting proteins” of the proteins and at time instance t2, we
have more additional information about the “No. of Domains” of the proteins. Using the infor-
mation available at time instance t0, i.e., “Localization”, we have the following equivalence clas-
ses.

fO1 ; O2 ; O8 g; fO3 ; O4 ; O5 ; O6 ; O7 g; ð8Þ

Using the above equivalence classes, we can compute the positive, negative and boundary

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 Protein function classification

Table 2. Property of the three regions with evolving information.

Localization time t0 Interacting proteins time t1 No. of Domains time t2
POS(C) ; {O3, O6} {O1, O3, O6}
NEG(C) ; {O4, O5, O7} {O2, O4, O5, O7, O8}
BND(C) {O1, O2, . . ., O8} {O1, O2, O8} ;
doi:10.1371/journal.pone.0171702.t002

regions using Eqs (5)–(7). The three regions are given by,

POSðCÞ ¼ ;;
NEGðCÞ ¼ ;; ð9Þ
BNDðCÞ ¼ fO1 ; O2 ; O3 ; O4 ; O5 ; O6 ; O7 ; O8 g;

In the same way we can compute the three regions at time instances t1 and t2, when we have
additional information in the form of “interacting proteins” and “No. of Domains”. Table 2
summarizes the three regions corresponding to the information available at the three instances
of time. Looking at the three regions for the different time instances, we may note that objects
in the boundary region are decreasing and are becoming part of the positive or negative
regions as more information is available at time instances of t1 and t2. In other words, the addi-
tional information about the “interacting proteins” and “No. of Domains” of the objects has
increased the size of the positive and negative regions. This means that we can make more
decisions in the form of acceptance or rejection when the level of available information
increases. In this article, we argue that this property of three-way decision making can be quite
useful for making decisions on protein functions classification.
In order to see the same phenomena visually, we include Fig 3. In each sub figure, the
green, red and orange colours represents the positive, negative and boundary regions. The cir-
cle represents a certain concept and the small rectangles depict the equivalence classes. From
Fig 3(a), we have least information and in Fig 3(c), we have most information. In Fig 3(b), we
have moderate level information. We may note that as information matures, we have finer

Fig 3. The three regions with evolving information. The sub-figures from left to right should be read as a, b and c respectively.
doi:10.1371/journal.pone.0171702.g003

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 Protein function classification

level details leading to refined partitions. This is shown by the smaller sized boxes in Fig 3(b)
and 3(c). The finer level details due to additional information enables us to move some of the
equivalence classes from boundary to either positive or negative regions thereby increasing
their respective sizes. This leads to fine tuning of positive and negative regions and we gradu-
ally converge to the concept, i.e., the circle (Fig 3(c)).

Three-way decisions using probabilistic rough sets

The conventional rough set model (outlined in Section Three-way Decisions using Rough
Sets) provide a useful approach for inducing and making three-way decisions. However, this
conventional rough sets model which is also sometimes referred to as Pawlak rough set model
suffers from a key limitation. Researchers argue that the conditions in the upper and lower
approximations may be too strict when it comes to real applications. Specifically the conditions
in Eqs (3) and (4), i.e., [x]  C and [x] \ C 6¼ Ø reflecting whether [x] is fully contained in C
and whether [x] has some overlap with C, respectively, may be too restricted in the sense that
they ignore the degree of an overlap between a set and a concept. To overcome this difficulty,
many researchers proposed different extensions of rough sets. The probabilistic rough sets rep-
resent one class of such extensions and include decision-theoretic rough sets, variable preci-
sion rough sets, 0.5-probabilistic rough sets, Bayesian rough sets, information-theoretic rough
sets and game-theoretic rough sets.
The general form of probabilistic rough sets resulted from the studies on decision-theoretic
rough sets [56, 57]. The probabilistic lower and upper approximations for a concept C are
defined using a pair of thresholds (α, β) as [58],
apr ða;bÞ ðCÞ ¼ fx 2 U j PðCj½xŠÞ  ag; ð10Þ

apr ða;bÞ ðCÞ ¼ fx 2 U j PðCj½xŠÞ > bg; ð11Þ

where P(C|[x]) denotes the conditional probability of a concept C with an equivalence class
[x]. Given that an object x 2 [x], the conditional probability highlights the evaluation of an
object x to be in C. The three rough set regions based on lower and upper approximations are
defined as,
POSða;bÞ ðCÞ ¼ fx 2 UjPðCj½xŠÞ  ag; ð12Þ

NEGða;bÞ ðCÞ ¼ fx 2 UjPðCj½xŠÞ  bg; ð13Þ

BNDða;bÞ ðCÞ ¼ fx 2 Ujb < PðCj½xŠÞ < ag: ð14Þ

The POS(α,β)(C), NEG(α,β)(C) and BND(α,β)(C) in Eqs (12)–(14) are referred to as positive, neg-
ative and boundary regions, respectively. Based on how these thresholds are determined and
interpreted we have different probabilistic rough set models.
To demonstrate the use of three-way decisions for proteins functions classification, we
focus on two probabilistic rough set models, namely, GTRS [25–27] and ITRS [59]. These two
models have at least two advantages over other models.
• Firstly, compared to some of the earlier probabilistic models, such as, 0.5-probabilistic rough
set model and (0.5, β) model, where due to restricted pairs of thresholds, the determination
and interpretation of thresholds are ignored, the GTRS and ITRS allows for investigation
and examination of thresholds based on different aspects.

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 Protein function classification

• Secondly, unlike other models that require user intervention to set the thresholds, such as,
decision-theoretic rough sets and variable precision rough sets, the GTRS and ITRS can be
used to learn and set the thresholds automatically when combined with some typical search
mechanism [25].
For the sake of being complete, we briefly explain and discuss the GTRS and ITRS models.
Three-way decisions using game-theoretic rough sets. The game-theoretic rough sets or
GTRS utilizes game-theoretic formulation to determine thresholds of probabilistic rough sets
[26, 27]. In particular, the thresholds are interpreted based on a tradeooff solution between
multiple criteria employed in a game setting for analyzing rough sets [25–27]. A typical game
in GTRS has three essential components, i.e., game players, strategies and payoff or utility
functions. These components are generally represented as a tuple {P, S, u}. We now explain
each of them.
Game players: The players in the game are denoted by a set P. Generally, there can be n
players in a game. However, for the sake of simplicity, a two player game is commonly consid-
ered in GTRS. Based on the overall game objective and goals, we may have different types of
game players. For instance, in a previous game for analyzing region uncertainty, the players
were defined as the uncertainty of the immediate and deferred decision regions and in another
game that seek for a balanced rough set model, the players of accuracy and generality were
used [25, 60]. In general, the players in the game are selected to reflect the overall purpose of
the game. In GTRS, the players are defined as different aspects and properties of rough sets
based classification and decision making such as accuracy, generality, precision and
uncertainty.
Strategies: Each player in the game participate by playing different strategies. The set of
strategies available to player i is denoted by Si. The Cartesian product of all possible strategy
sets is denoted by S = S1 × S2 × . . . × Sn, where S contains ordered pairs of the form (s1, s2, . . .,
sn) such that s1 2 S1, s2 2 S2 and sn 2 Sn. Each order pair in S is called a strategy profile and rep-
resents a certain situation encountered in a game.
The strategies in GTRS are realized as different changes and modifications in the (α, β)
thresholds. Depending on the initial values of thresholds, we may have different types of strate-
gies. For instance, if the initial values of (α, β) are set to (1, 0.5), then the strategies may be for-
mulated as decreasing levels of α and β. Alternatively, when the initial values of (α, β) are set to
(1, 0), then the strategies may be formulated as decreasing levels of α and increasing levels of β.
Please note that in order to keep the regions disjoint, it is assumed that 0  β < α  1.0. The
strategies of the players in a game lead to effective modification of the thresholds which ulti-
mately determines the final configuration of the thresholds.
Payoff functions: The payoff functions for the players are represented by a set u = (u1, . . .,
un). Each ui is a real valued utility function for player i and it maps the strategy profiles to real
values, i.e., ui: S 7! <. In particular, the payoffs reflect the utilities of performing or selecting a
certain strategy. Recall the game players in GTRS which are represent different aspects or
properties of rough sets, the payoff function for a certain player is based on particular measure
employed for evaluating its respective property.
In a game setting, every player wants to perform a strategy that will maximize its payoff.
The selected strategies of the players however affect their opponents payoffs. The game solu-
tion is used to choose a balanced and trade off point based on the utilities of all the players.
The game solution of Nash equilibrium is commonly used in GTRS for this purpose.
Considering a strategy profile s−i = (s1, s2, . . ., si−1, si+1, . . ., sn), which means a strategy pro-
file without player i strategy. Moreover, the strategy profile (s1, s2, . . ., sn) may be denoted in
revised notation as (si, s−i). The strategy profile (s1, s2, . . ., sn) = (si, s−i) is a Nash equilibrium if

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 Protein function classification

[61],

0 0 0
8i; 8si 2 Si ; ui ðsi ; s i Þ  ui ðsi ; s i Þ; whereðsi 6¼ si Þ ð15Þ

This means that for all players i, their respective strategies, i.e., si is the best response to s−i. In
other words, a strategy profile constitutes a Nash equilibrium when no player is benefited from
changing his strategy alone.
The above game description is used in GTRS to formulate a game. However, with a single
one time and non-repeated game, we may not be able to reach effective thresholds that fulfill
the demands of the underlying applications. We need to repeat the game. The essential idea is
to repeatedly modify and refine the thresholds, until we achieve certain performance criteria.
By formulating a game and utilizing the notions such as game solution and repetitive games,
the GTRS seek for an effective configuration of the threshold levels that are employed in the
probabilistic rough sets framework to induce three-way decisions.
Three-way decisions using information-theoretic rough sets. The Information-theo-
retic rough sets (or ITRS) approach the threshold determination issue from the viewpoint of
minimizing the information uncertainty of the probabilistic rough set regions [59]. Let ΔP(α,
β), ΔN(α, β) and ΔB(α, β) denote the overall uncertainties of the probabilistic positive, negative
and boundary regions respectively. The ITRS is based on minimization or optimization of the
following problem.

arg min Dða; bÞ; where;

ða;bÞ
ð16Þ
Dða; bÞ ¼ DP ða; bÞ þ DN ða; bÞ þ DB ða; bÞ

Please be noted that we used slightly modified notations that were reported in [25]. Eq (16)
suggests that we seek thresholds (α, β) that will minimize the uncertainty of the three regions.
The overall uncertainty in Eq (16) is typically considered as an average uncertainty of the
three regions [59].

DP ða; bÞ ¼ PðPOSða;bÞ ðCÞÞdP ða; bÞ; ð17Þ

DN ða; bÞ ¼ PðNEGða;bÞ ðCÞÞdN ða; bÞ; ð18Þ

DB ða; bÞ ¼ PðBNDða;bÞ ðCÞÞdB ða; bÞ; ð19Þ

where δP(α, β), δN(α, β) and δB(α, β) are the uncertainties of the three regions which may
be computed and interpreted using different measures of uncertainties. Moreover,
P(POS(α,β)(C)), (POS(α,β)(C)) and P(POS(α,β)(C)) are the probabilities of the three regions. Two
measures, i.e., Shannon entropy and gini coefficient are being previously employed for inter-
preting and measuring the uncertainties of the three regions, i.e., δP(α, β), δN(α, β) and
δB(α, β). We now define each of them.
Consider a partition based on a concept C, given by, πC = {C, Cc} and another partition with
respect to the thresholds (α, β), given by, π(α,β) = {POS(α,β)(C), NEG(α,β)(C), BND(α,β)(C)}. The
uncertainty in πC with respect to the three probabilistic regions based on Shannon entropy is

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 Protein function classification

given by, [59],

dP ða; bÞ ¼ HðpC jPOSða;bÞ ðCÞÞ ¼ PðCjPOSða;bÞ ðCÞÞ log PðCjPOSða;bÞ ðCÞÞ
ð20Þ
PðCc jPOSða;bÞ ðCÞÞ log PðCc jPOSða;bÞ ðCÞÞ;

dP ða; bÞ ¼ HðpC jNEGða;bÞ ðCÞÞ ¼ PðCjNEGða;bÞ ðCÞÞ log PðCjNEGða;bÞ ðCÞÞ

ð21Þ
PðC jNEGða;bÞ ðCÞÞ log PðCc jNEGða;bÞ ðCÞÞ;
c

dP ða; bÞ ¼ HðpC jBNDða;bÞ ðCÞÞ ¼ PðCjBNDða;bÞ ðCÞÞ log PðCjBNDða;bÞ ðCÞÞ

ð22Þ
PðC jBNDða;bÞ ðCÞÞ log PðCc jBNDða;bÞ ðCÞÞ:
c

Where we used the additional notations H(πC|POS(α,β)(C)), H(πC|POS(α,β)(C)) and H(πC|

POS(α,β)(C)) to be consistent with the earlier notations [59]. The measure of gini coefficient is
also used in the same way to determine the uncertainties of the three regions [62]. The uncer-
tainties of the three regions are computed as [62],
2
dP ða; bÞ ¼ GðpC jPOSða;bÞ ðCÞÞ ¼ 1 PðCjPOSða;bÞ ðCÞÞ
2
ð23Þ
PðCc jPOSða;bÞ ðCÞÞ ;

2
dN ða; bÞ ¼ GðpC jNEGða;bÞ ðCÞÞ ¼ 1 PðCjNEGða;bÞ ðCÞÞ
2
ð24Þ
PðCc jNEGða;bÞ ðCÞÞ ;

2
dB ða; bÞ ¼ GðpC jBNDða;bÞ ðCÞÞ ¼ 1 PðCjBNDða;bÞ ðCÞÞ
2
ð25Þ
PðCc jBNDða;bÞ ðCÞÞ :

Please note again that the notation G(πC|BND(α,β)(C)), G(πC|BND(α,β)(C)) and

G(πC|BND(α,β)(C)) are being used for the sake of being consistent with the previous notations
[62].
The ITRS is generally combined with a searching mechanism to determine effective thresh-
olds. In particular, the minimization of overall uncertainty in Eq (16), is used to guide the
search towards optimal thresholds. Recently, the gradient descent approach was suggested in
this regards [59].

Three-way decision algorithm for classifying protein

In this section, we look at three-way decision approach from implementation perspective.
Algorithm 1 is presented for this purpose. The algorithm explains how three-way decisions
can be used in classifying proteins with evolving information.

Algorithm 1 Iterative Three-way decision making algorithm

Input: An information table containing a new feature and POS(α,β)(C),
NEG(α,β)(C), and BND(α,β)(C) based on information from previous features
Output: Updated regions, POS(α,β)(C), NEG(α,β)(C) and BND(α,β)(C)
1: if QP(α, β)  c1 and QN(α, β)  c2 then
2: Determine thresholds (α0 , β0 ) using GTRS and ITRS for information table
with U = BND(α,β)(C)
3: POS(α0 , β0 )(C) = {x 2 BND(α,β)(C)|P(C|[x])  α0 }
4: NEGða0; b0 Þ ðCÞ ¼ fx 2 BNDða;bÞ ðCÞjPðCj½xŠÞ  b0 g

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 Protein function classification

0 0
5: BND(α0 , β0 )(C) = {x 2 BND(α,β)
S(C)|β < P(C|[x]) < α }
6: POS(α,β)(C) = POS(α0 , β0 )(C)SPOS(α,β)(C)
7: NEG(α,β)(C) = NEG(α0 , β0 )(C) NEG(α,β)(C)
8: BND(α,β)(C) = BND(α0 , β0 )(C)−BND(α,β)(C)
9: else
10: Determine thresholds (α, β) using GTRS and ITRS.
11: POS(α,β)(C) = {x 2 U|P(C|[x])  α}
12: NEG(α,β)(C) = {x 2 U|P(C|[x])  β}
13: BND(α,β)(C) = {x 2 U|β < P(C|[x]) < α}
14: end if
15: return POS(α,β)(C), NEG(α,β)(C), BND(α,β)(C)

The algorithm accepts information table containing information about a new feature and
the three regions based on the previous features, i.e., positive, negative and boundary regions
denoted as POS(α,β)(C), NEG(α,β)(C), and BND(α,β)(C), respectively. In line 1, the algorithm
evaluates the positive and negative regions by employing some quality criteria denoted as
QPOS(α,β) and QNEG(α,β) (representing some quality related aspect of the positive and negative
regions, respectively). These notations are introduced to represent the general notion of any
criteria that is employed for evaluating the three regions. They may be interpreted in terms of
cost, risks, uncertainty, accuracy or precision. The quality of the regions may be measured
based on the notions such as risks, cost, uncertainty, accuracy or precisions. As discussed in
the previous subsection titled Three-way Decisions and Evolving Information, when the fea-
tures evolve, the positive region gradually converges to the concept C (i.e., more precisely
reflect the region representing the concept) and the negative region gradually converges to the
complement of the concept Cc (i.e., more precisely reflect the region not in the concept),
respectively. As a result, the quality of the two regions improves. As improvement in quality is
a gradual process in this case, at the current level of information, the quality of the positive and
negative regions may or may not be effective (please be noted that the term effective here may
have different interpretation based on the underlying applications). We deal with these two
cases separately.
If the quality of the regions are above some acceptable levels c1 and c2, we will only examine
the objects in the boundary region and will not further investigate the positive and negative
regions. The boundary is expected to shrink further as we have access to new features. In any
other case, we will examine the full information table to obtain the three regions. In other
words, we are not satisfied with the quality of the positive and negative regions (they are below
the levels c1 and c2) and we expect that additional information may improve their respective
quality levels. We first deal with the former case. In line 3, we determine thresholds based on
the reduced information table with U = BND(α,β)(C). As new information becomes available in
the form of a new feature, we may be able to confidently classify further objects in the bound-
ary. This is shown in line 4-7 where we further divide the objects in the boundary region. In
line 6-8, we update the three regions based on further examination of the boundary. From line
10-13 we examine the case when the positive and negative regions based on the previous
knowledge were not of acceptable quality. We therefore examine the full information table and
update the three regions accordingly. The Fig 4 represents the essential ideas of the algorithm
1 in diagrammatic form.
It may be noted that the constants c1 and c2 may be defined in different ways depending on
the application needs and requirements. For instance, if we want to reduce the processing
overload, we may define them moderately. On the other hand, if processing overload is not an
issue and we are more concerned about the accuracy, then we may define them more strictly.
Other ways in which they may be defined are by making comparison with the quality of the

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 Protein function classification

Fig 4. Visualization of iterative three-way decision making algorithm.

doi:10.1371/journal.pone.0171702.g004

regions obtained with the standard Pawlak models or other known models in the domains or
by considering the improvement in quality based on the new features.

Experiment setup
Data preparation
To evaluate the use of three-way approach, we examine the application of three-way decisions
on well studied Saccharomyces cerevisiae species proteins [63, 64], obtained from most widely
used Uniport database [29]. From various classification schemes developed to standardize the
descriptions of protein functions, we chose the state of the art Gene Ontology (GO) [30] classi-
fication scheme. The gene ontology is a structured, controlled vocabulary of protein functions
also called terms. GO terms provide consistency in annotating protein roles in the cellular con-
text. It is arranged in a DAG (please refer to Section Background) structure in which each
node of the graph represents a unique functional term and each term is arranged in a parent
child relationship with other terms. The child term either is a special case of the parent or is a
part of the parent process i.e., a sub-process or component. For the evaluation of our method-
ology we operate on molecular function category of gene ontology. To reveal the evolving
nature of biological information, we present features in the order in which they are evolved
over the time i.e., most basic type of information is presented first and so on [3]. For classifying
a protein into one or more molecular function terms of gene ontology, we retrieve ten different
types of features from varied biological databases. Each feature is helpful in characterizing one
or more functional categories and is represented by the symbol Fi.
Protein Sequence Length (F1): In every cell, genes are converted into proteins via the pro-
cesses of transcription and translation also called the central dogma of molecular biology. The
end product of these processes is a sequence built from twenty amino acids, and is commonly
known as the primary structure of a protein. The amino acid sequence is the most basic type of
information available about a protein, as it can provide concrete evidence about different char-
acteristics of a protein such as its binding sites, sub-cellular localization, structure and

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 Protein function classification

function. To quantify these biological aspects of a protein, we use feature (namely F1), as the
length of protein sequence which is extracted from Uniprot database [29].
Protein Localizations (F2): The location of a protein in the cell can also be associated with
its function. Co-localized proteins are more likely to be part of same molecular activity. Like-
wise, proteins localizing in many different locations can be part of diverse activities. To capture
this aspect, we calculate feature F2 as the number of locations a protein can localize. The pro-
tein localization data is retrieved from the Uniprot database [29].
Biological Processes (F3): A biological process refers to the series of events performed by
one or more assemblies of molecular functions with a defined beginning and end. A protein
participating in many biological processes is more likely to have many molecular level roles.
Thus the number of biological processes of a protein can also be used to capture the molecular
level activities of a protein. As a third feature (F3), we count the number of biological processes
of a protein. It is obtained by retrieving counts of Biological Process ontology terms from the
Gene Ontology database [30].
Number of Interacting Proteins (F4): For calculating the fourth feature of our method,
namely F4, we use genome wide protein-protein interactions (PPI) data to predict proteins
function. In a living cell, protein-protein interactions are amongst the most ubiquitous types
of interactions and their precise knowledge helps in understanding the activities performed by
a protein as well as the processes it is part of. A protein having many different interacting part-
ners can be said to be part of many different functions. Thus the number of interactions (F4) of
a protein can be linked to the wide variety of activities it performs. We obtain PPI data from
most widely used PPI databases, namely, IntAct [65] and STRING [66]. Since protein-protein
interactions databases are noisy, we only consider interactions that are experimentally verified
and are supported by at least two experiments.
Number of Domains (F5): Protein domains are the sequential units that fold in a particular
shape, making independent structures in different proteins. Several classification schemes
have been proposed e.g., [67] to define and demarcate different domains of which some based
on clustering conserved subsequences into related domain families, others on known distinct
structural classes [68]. One of the most famous and widely used domain classification schema
is the Interpro database [69]. InterPro database contains diagnostic signatures of protein
sequences consisting of models e.g., regular expressions models, Hidden Markov Models etc.,
which describe protein domains found within sequence. Domains are the most important fea-
ture among relevant sequence features of a protein that associate it to a particular kind of func-
tions. To integrate domain relevance we also use as a feature (namely F5) the number of
Interpro conserved domains within a query protein sequence.
Number of Conserved Motifs (F6): A motif is a conserved amino acid sequence pattern in
a protein sequence that may be associated to a specific function. These subsequences may
often contain small “gaps” of fixed or variable lengths among amino acids of the subsequence.
The knowledge of exact patterns of motifs and their functions is helpful in the understanding
of structure and function of related proteins in which such motifs may appear. For example, if
a motif of a certain family is present in a protein sequence then it will make it highly probable
to functionally associate that protein with the functions of that motif i.e., we can associate pro-
teins with functions by merely checking the presence of certain motifs. Thus in our technique,
as sixth feature (F6) we count the number of conserved motifs in a protein sequence using Pro-
site motif database [70].
Number of Protein Structures (F7): A protein’s primary structure consists of sequence of
amino acids. These amino acids due to their varied physical and chemical properties as well as
the presence of different participant cellular forces, assumes a unique configuration in three-
dimensional space. This stable configuration of proteins is also called the tertiary structure of

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 Protein function classification

proteins. This final configuration or structure of a protein is strongly correlated to its function,
because in many biological processes, the interacting proteins have to come into physical con-
tact in order to accomplish the desired function. The structure of a protein also determines
many of its functional characteristics, for example its inter-facial binding sites, the specific
ligands it binds to, cellular localizations, as well as other proteins it can interact with. Among
all the structural databases PDB (Protein Data Bank) [71] is by far the most reliable, wide-rang-
ing as well as popular repository for experimentally derived protein 3D structures. We query
the PDB database to obtain the number of experimentally determined structures associated to
a protein under investigation and use this information as a feature (namely F7) to characterize
its function.
Molecular Weight of Protein (F8): Although weight of a protein is not strongly related to
its function but in some cases it can be used to generally group them into broader functional
categories. We retrieve Molecular weight rounded to the nearest mass unit (Dalton) from Uni-
prot Database [29] and use it as a feature (namely F8) for our 3-way classifier.
Number of Interfacing Residues in Protein Structure (F9): Many proteins bind together
and form multi-protein complexes. Different proteins in the complex perform different func-
tions. These functions are associated with the number of residues on a protein’s interface that
enables it to stabilize, bind and form complexes. Owing to the significance of interfacing resi-
dues we utilize a structural feature i.e., the number of residues on the protein’s interface to
characterize function of a protein. The interfacing residues can vary for various functional
activities. To capture this aspect we used PDBe PISA server [72], to retrieve the number of pre-
dicted interfacing residues and use it as feature (namely F9) for our 3-way classifier.
Binding sites in the Predicted Interface (F10): A protein’s physical interaction with other
molecules, determines its biological activities. For example antibody proteins selectively bind
to viruses or bacteria to choose them for destruction, the hexokinase protein binds to ATP
molecule as well as with glucose molecule in order to catalyze their chemical reaction, and so
on. Without any doubt almost all proteins stick, or bind, to other molecules in order to per-
form their activities at molecular level. Some proteins bind very tightly while others bind for a
short period of time depending on their specificity as well as the molecular task they have to
perform. Each protein can usually bind to one or few other molecules determined by the
nature of binding residues (also called binding sites) at its surface. To determine the specificity
of a protein for binding and performing wide variety of functions we calculate a feature
(namely (F10), which is the number of binding sites on its surface that are predicted using
PDBeFold Server [73].
The above features namely, F1 to F10, are extracted using the Feature Extractor module
(already described in Section An Architecture of Protein Function Classification with
Three-way Decisions), from the world wide biological databases using the knowledge discov-
ery module. The Feature Extractor module also has the capability to incorporate any new fea-
ture, say F11 in the predictive task. To imitate the ever evolving nature of biological
information, we selected and ranked features from most basic type to the latest type i.e, F1
namely, sequence similarity, is a basic type of feature and F10 namely, number of binding sites
on a protein interface, is a specific feature known after information evolution.

Three-way approaches used in the experiments

We performed experiments with five three-way decision making approaches based on GTRS
and ITRS. Specifically three of these approaches are based on GTRS and two of them are based
on ITRS.

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 Protein function classification

The three approaches with GTRS are based on different games that are formulated based
on description in Section Three-way Decisions using GTRS. The essential difference in these
games are the consideration of different types of game players. Two of these games are based
on examining a balance between the uncertainties of probabilistic rough set regions. These
games are based on two players, namely, immediate decision region, denoted as I and deferred
decision region, denoted as D. The player I reflects the collective uncertainty in probabilistic
positive and negative regions and the player D denotes the uncertainty in the probabilistic
boundary region. By realizing changes in thresholds as game strategies, the players in a game
compete in a game by selecting appropriate changes in the thresholds which are used in deter-
mining the final settings of the thresholds. Two games are constructed with these game players,
i.e., player I and D by realizing different interpretation and computation of uncertainty. In one
game, the uncertainty is measured with the Shannon entropy and in another game it is mea-
sured with gini coefficient. These two games will be referred to as GTRSE and GTRSG, respec-
tively. These game were previously examined in the context of text categorization and medical
decision making [25, 62, 74]. The third game in GTRS is based on determining a trade off
between two aspects of rough sets based classification, namely, accuracy and generality. This
game was previously examined in the context of recommender systems in [60]. We will refer
to this game as GTRS(A,G).
Two approaches are considered with the ITRS. These two approaches are ITRS based on
Shannon entropy and ITRS based on Gini coefficient as discussed in Section Three-way Deci-
sions using ITRS. We denote these approaches as ITRSE and ITRSG, respectively. Both of
these measures interpret the uncertainty in a different way and therefore will lead to different
thresholds.
In all experiments, we considered the top five most frequent protein functions in the data-
base. For each protein function (recall that each protein function is considered as a category),
we learn the probabilistic thresholds (α, β) and performed three-way decisions using the five
approaches discussed above in this section. We considered four feature sets. In each feature
set, we consider the features whose relevant information was previously available or which
emerged roughly at the same time. In particular, the first feature set comprise of F1, F2 and F3
(please refer to Section Data Preparation for their details). We denote the first feature set as
FS1. The second feature set denoted as FS2, is given by FS1 [ F4. The third and fourth feature
sets, denoted as FS3 and FS4 are given by FS3 = FS2 [ {F5, F6} and FS4 = FS3 [ {F7, F8, F9, F10},
respectively. Please be noted that the FS1 contains the oldest available information about pro-
teins while FS4 is the represents the most recent information comprising the previous knowl-
edge and newly evolved information. Finally, all the results are based on 10 folds cross
validation.

Results and discussion

Experimental results
We report the results of accuracy and generality for the considered three-way approaches. The
accuracy and generality may be defined as [24],
S
jðPOSða;bÞ ðCÞ \ CÞ ðNEGða;bÞ ðCÞ \ Cc Þj
Accuracyða; bÞ ¼ S ; ð26Þ
jPOSða;bÞ ðCÞ NEGða;bÞ ðCÞj

S
j POSða;bÞ ðCÞ NEGða;bÞ ðCÞj
Generalityða; bÞ ¼ ; ð27Þ
jUj

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 Protein function classification

Table 3. Results of accuracy and generality for GTRS.

Features GTRS(A,G) GTRSE GTRSG
Accuracy Generality Accuracy Generality Accuracy Generality
FS1 0.8031 0.2377 0.7938 0.2276 0.7969 0.2913
FS2 0.8058 0.3108 0.8077 0.2888 0.8071 0.3467
FS3 0.7808 0.6654 0.7853 0.6737 0.7807 0.6724
FS4 0.7815 0.6875 0.7797 0.6851 0.7807 0.6891
doi:10.1371/journal.pone.0171702.t003

The accuracy highlights the relative number of correct classification decisions for the objects
in the universal set and the generality reflects the relative number of objects for whom classifi-
cation decisions can be made. Table 3 shows the results obtained with the GTRS based
approaches. The rows of the table correspond to the results obtained with a particular set of
features and the columns correspond to results of accuracy and generality for different
approaches. The best results for accuracy and generality against each approach is presented in
bold. We may note that the best results for the generality for the three approaches are against
the highest feature set size. Moreover, the generality of the three approaches improve as the
feature set size is increased. In particular, the generality of GTRS(A,G) with lowest feature size is
23.77% and the highest feature set size is 68.75%. This represents a total increase of 44.98% in
generality. For the other two approaches, i.e., GTRSE and GTRSG, similar increases in general-
ity with values 45.75% and 39.78% are noted based on the lowest feature set size and highest
feature set size. Since the features represent the available level of information for predicting
protein functions. We may conclude from these results that as the level of information
improves (i.e., as we include more features), we are able to make classification decisions for
more proteins.
Let us now look at the results of accuracy in Table 3. We may observe that in general, the
values of accuracy decrease slightly as we move from lower to higher feature set sizes. How-
ever, compared to the generality, we do not have significant different between these values. For
the three approaches, i.e., GTRS(A,G), GTRSE and GTRSG, the differences between the values of
accuracy for the lowest and highest feature set sizes are 2.16%, 1.41% and 1.62%, respectively.
From the results of accuracy and generality, we may notice that by increasing the number of
features or the level of information, we are able to make more decisions while mainlining the
same or similar level of accuracy.
Table 4 shows the results obtained with the ITRS based approaches. The increase in general-
ity for the two approaches, i.e., ITRSE and ITRSG between the lowest feature set size and high-
est feature set sizes are 14.36% and 18.29%, respectively. The accuracy values for the ITRSE and

Table 4. Results of accuracy and generality for ITRS.

Features ITRSE ITRSG
Accuracy Generality Accuracy Generality
FS1 0.8247 0.6008 0.8139 0.5972
FS2 0.8043 0.6296 0.8101 0.631
FS3 0.7927 0.7394 0.7878 0.7411
FS4 0.791 0.7444 0.7865 0.7801
doi:10.1371/journal.pone.0171702.t004

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 Protein function classification

Fig 5. Results of the positive, negative and boundary regions.

doi:10.1371/journal.pone.0171702.g005

ITRSG approaches are decreased by a small 3.37% and 2.74%, respectively as we increase the
feature set size. comparing these results with the GTRS based approaches, we may note that
the generality values of the ITRS approaches are significantly better than those obtained with
the GTRS based approaches. However, for accuracy there is no significant different between
ITRS and GTRS based approaches as both of them are around 80%. Despite some differences
in the results with the two approaches, the key observation noted earlier in the discussion of
GTRS based results holds for the results in the case of ITRS as well. We may notice again that
increasing the number of features or the level of information lead to better generality (which
implies more classification decisions) while maintaining the same or similar level of accuracy.
In order to highlight this observation, we constructed two figures.
Fig 5 shows the results of the positive, negative and boundary regions based on the GTRS
and ITRS based approaches. Each bar in the figure is split into three parts, representing the
positive, negative and boundary regions respectively. Each set of four bars corresponds to a
particular approach and is separated by a large space. The four bars are placed in increasing
order of feature set sizes. In each set of four bars, the leftmost bar corresponds to the least fea-
ture set size and the rightmost bar corresponds to the highest feature set size. We may note in
Fig 5, that as we increase the feature set sizes, the positive and negative regions grow in size
while the boundary regions shrinks. According to the definition of generality in Eq (27), the
union of the positive and negative regions represents the generality. This figure highlights the

PLOS ONE | DOI:10.1371/journal.pone.0171702 February 24, 2017 21 / 29

 Protein function classification

Fig 6. Accuracy and generality results of the GTRS based approaches.

doi:10.1371/journal.pone.0171702.g006

same fact, noted earlier in the previous discussion, i.e., we are able to make more classification
decisions for proteins as the level of information increases (or number of features increases).
Please be noted that in probabilistic rough sets, it is not always necessary that the addition of
features will increase the positive and negative regions. However, we want to emphasize the
fact that it will result in improvement in the quality of the regions.
Figs 6 and 7 summarizes the results of accuracy and generality for the considered
approaches. The green colour in these figures represent the accuracy and the red colour indi-
cate the generality. The values of accuracy and generality are reported for all four feature sets
described in the previous section. It may be noted that for all the approaches, the generality
improves as we use higher number of features. However, on the other hand the accuracy is not
affected significantly. This means that by increasing the features, we are able to improve the
generality while maintaining the similar level of accuracy.

PLOS ONE | DOI:10.1371/journal.pone.0171702 February 24, 2017 22 / 29

 Protein function classification

Fig 7. Accuracy and generality results of the ITRS based approaches.

doi:10.1371/journal.pone.0171702.g007

Comparison with other approaches

In this section, we compare our method to the most widely used group of function prediction
techniques. The first choice of comparison is a most recent function prediction tool, namely
INGA (Interaction Network GO Annotator) [75], which is a state of the art tool to predict pro-
tein functions. INGA is based on a consensus strategy that maximizes the F-score by utilizing
protein interaction networks, sequence similarity as well as domain information for protein
function prediction. Since, information such as protein domains, protein interaction net-
works, sequence similarity are directly related to protein function and are at the heart of over-
whelming majority of methods that integrate it for protein function prediction, we chose to
compare our method against this function prediction tool.
To attain the most accurate comparative results, we run our algorithm for wider range of
target classes of the molecular function ontology in a ten-fold cross-validation setting. We
present the comparative results (i.e., Accuracy and Generality as defined in Eq (26)) of INGA
and our method in Table 5 when tried on Saccharomyces cerevisiae proteins. Clearly, our

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 Protein function classification

Table 5. Comparison of the proposed three way classification method with top performing methods
of the field. The target classes comprise of broader gene ontology terms for Saccharomyces cerevisiae spe-
cies proteins.
Method’s Name Generality Accuracy
Three way decision using GTRS 68% 78.40%
Three way decision using ITRS 74% 79.2%
INGA (Interaction Network GO Annotator) tool [75] 60% 57%
Jones-UCL [76] 62% 59.5%
Argot [76] 61% 59.4%
BLAST Annotation Transfer (baseline method) [76] 78% 38%
doi:10.1371/journal.pone.0171702.t005

method outperforms IGNA in both aspects. The strength of our method mainly comes from
the fact that it is able to defer instances (i.e., proteins) for which there is less characterization
evidence at present, thus improving prediction accuracy.
In order to get further insight into the relative performance, we also consider some results
that were reported on similar problem. The most recent and well known schemes proposed for
the prediction of protein functions are evaluated in the CAFA (Critical Assessment of protein
Function Annotation) challenge [76]. The CAFA challenge is conducted after every two years
to have comparative evaluation of top schemes for the prediction of protein functions. One of
the best sequence alignment algorithm (i.e., BLAST), which is also used as a baseline scheme
for annotation transfer, achieved an accuracy of 38% during the CAFA challenge, when tried
on molecular function category of GO [76]. Likewise, the top schemes of the challenge have
reported to have an accuracy of 59.5% and 59.4%, respectively [76], when tested against hetero-
geneous ontology classes. On the other hand, our method have achieved an overall accuracy of
80% when tried for the same target classes, depicting a significant gain in terms of prediction
accuracy.
Another method, that is more recently proposed, by Mitrofanova et al. in [8], combines
inter-species homology data for protein function prediction and reported an accuracy of
97.7% when tried on Saccharomyces cerevisiae proteins. However, the results of this method
cannot be directly compared with our approach for a number of reasons. Firstly, this method
operates on fixed ontology sizes thus giving results for only 16 GO terms (target classes) out of
more than 30,000 GO terms. Secondly, the fixed GO terms chosen by the authors limit perti-
nence of their method to proteins directly annotated to those GO terms, hence limiting the
applicability of their algorithm to only a small number of proteins (hence, significant reduction
in generality). On the other hand, our algorithm has much wider GO coverage and results pre-
sented include all the yeast proteins.
As a final remark, it is pertinent to mention here that although three way classification
achieved far better results than the earlier proposed schemes but the main purpose of this
study was not the optimization of performance (in terms of precision or accuracy) of the ear-
lier schemes. But rather it should be looked at from the perspective of an examination, feasibil-
ity and appropriateness of considering three way classification schemes based on evolving
biological information for the task of protein function predictions.
In conclusion, the three way approaches considered in this study achieve an average accu-
racy of 80%. The incorporation of future information is useful as it improves the generality or
applicability of the models while maintaining similar level of accuracy. In particular, there is
an increase in generality by more than 40% for the GTRS based approaches and more than

PLOS ONE | DOI:10.1371/journal.pone.0171702 February 24, 2017 24 / 29

 Protein function classification

14% for the ITRS based approaches. From the general trend in the results, it is suggested that
as more information becomes available, the generality may improve further. These results
advocate for the use of three-way approaches for protein functions classification.

Conclusion
Proteins are involved in almost every biological phenomena and the precise knowledge of
their functions plays an essential role in understanding biological processes. Intelligent mecha-
nisms are generally employed to assign and predict functions of proteins. The technological
advancements are continuously resulting in new information and features describing protein
functions which in turn can be utilized for improving the quality of protein function predic-
tions. An important issue in this context is to develop effective classification schemes and
models for classifying protein functions by incorporating evolving information. We propose a
three-way decision making approach to address this issue. The approach includes a deferment
decision option which is practiced in situations characterized by insufficient and incomplete
information. In particular, we considered probabilistic rough sets based models i.e., game-the-
oretic rough sets and information-theoretic rough sets for inducing and making three-way
decisions. An architecture of protein function classification with three-way decisions is also
proposed and explained. Experimental results on dataset from Uniprot database indicate that
as the level of biological information increases, the number of deferred cases are reduced while
maintaining similar level of accuracy. In particular, an average accuracy of 80% (±%2) was
reported for the considered approaches with an average generality improvement of 33% (±%5)
as we increase features.
We investigated the probabilistic rough sets which is one possible way for inducing three-
way decisions. Other approaches such as shadowed sets, statistical testing, interval sets and
ortho-pairs may also be examined to investigate the potential benefits of three-way approach
to protein function classification. Moreover, the three-way approach for protein function clas-
sification may further be evaluated and extended by incorporating new features resulting from
next generation sequencing data or from other high throughput experiments.

Supporting information
S1 File. “S1_File.zip”. The code (Python/Bash/Matlab) and data files along with instructions
are provided as a zip file.
(ZIP)

Acknowledgments
The third author was partially supported by Discovery Grant from NSERC Canada. We are
also thankful to the Higher Education Commission of Pakistan for providing student grant
under the SRGP (Startup Research Grant Program) initiative. There was no additional external
funding received for this study.

Author Contributions
Conceptualization: HU NA JY AB.
Formal analysis: HU NA JY AB.
Investigation: HU NA JY AB.
Methodology: HU NA JY AB.

PLOS ONE | DOI:10.1371/journal.pone.0171702 February 24, 2017 25 / 29

 Protein function classification

Project administration: HU NA JY AB.

Software: HU NA.
Supervision: JY AB.
Validation: HU NA.
Writing – original draft: HU NA JY AB.
Writing – review & editing: HU NA JY AB.

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