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.
 Computational Toxicology

Volume II

Edited by

Brad Reisfeld
Department of Chemical and Biological Engineering and School of Biomedical Engineering
Colorado State University, Fort Collins, Colorado, USA

Arthur N. Mayeno
Department of Chemical and Biological Engineering,
Colorado State University, Fort Collins, Colorado, USA
Editors
Brad Reisfeld Arthur N. Mayeno
Department of Chemical Department of Chemical
and Biological Engineering and and Biological Engineering
School of Biomedical Engineering Colorado State University
Colorado State University Fort Collins, Colorado, USA
Fort Collins, Colorado, USA

ISSN 1064-3745 ISSN 1940-6029 (electronic)

ISBN 978-1-62703-058-8 ISBN 978-1-62703-059-5 (eBook)
DOI 10.1007/978-1-62703-059-5
Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2012946102

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Preface

Rapid advances in computer science, biology, chemistry, and other disciplines are enabling
powerful new computational tools and models for toxicology and pharmacology. These
computational tools hold tremendous promise for advancing applied and basic science,
from streamlining drug efficacy and safety testing to increasing the efficiency and effective-
ness of risk assessment for environmental chemicals. These approaches also offer the
potential to improve experimental design, reduce the overall number of experimental trials
needed, and decrease the number of animals used in experimentation.
Computational approaches are ideally suited to organize, process, and analyze the vast
libraries and databases of scientific information and to simulate complex biological phe-
nomena. For instance, they allow researchers to (1) investigate toxicological and phar-
macological phenomena across a wide range of scales of biological organization
(molecular cellular organism), (2) incorporate and analyze multiple biochemical and
biological interactions, (3) simulate biological processes and generate hypotheses based
on model predictions, which can be tested via targeted experimentation in vitro or in vivo,
(4) explore the consequences of inter- and intra-species differences and population varia-
bility on the toxicology and pharmacology, and (5) extrapolate biological responses across
individuals, species, and a range of dose levels.
Despite the exceptional promise of computational approaches, there are presently very
few resources that focus on providing guidance on the development and practice of these
tools to solve problems and perform analyses in this area. This volume was conceived as
part of the Methods in Molecular Biology series to meet this need and to provide both
biomedical and quantitative scientists with essential background, context, examples, useful
tips, and an overview of current developments in the field. To this end, we present a
collection of practical techniques and software in computational toxicology, illustrated with
relevant examples drawn principally from the fields of environmental and pharmaceutical
sciences. These computational techniques can be used to analyze and simulate a myriad of
multi-scale biochemical and biological phenomena occurring in humans and other animals
following exposure to environmental toxicants or dosing with drugs.
This book (the second in a two-volume set) is organized into six parts each covering a
methodology or topic, subdivided into chapters that provide background, theory, and
illustrative examples. Each part is generally self-contained, allowing the reader to start
with any part, although some knowledge of concepts from other parts may be assumed.
The final part provides a review of relevant mathematical and statistical techniques. Part I
explores the critical area of predicting toxicological and pharmacological endpoints, such as
mutagenicity and carcinogenicity, and demonstrates the formulation and application of
quantitative structure–activity relationships (QSARs) and the use of chemical and endpoint
databases. Part II details approaches used in the analysis of gene, signaling, regulatory, and
metabolic networks, and illustrates how perturbations to these systems may be analyzed in
the context of toxicology. Part III focuses on diagnostic and prognostic molecular indica-
tors and examines the use of computational techniques to utilize and characterize these
biomarkers. Part IV looks at computational techniques and examples of modeling for
risk and safety assessment for both internal use and regulatory purposes. Part V details
approaches for integrated systems modeling, including the rapidly evolving development

v
vi Preface

of virtual organs and organisms. Part VI reviews some of the key mathematical and
statistical methods used herein, such as linear algebra, differential equations, and least-
squares analysis, and lists other resources for further information.
Although a complete picture of toxicological risk often involves an analysis of environ-
mental transport, we believe that this expansive topic is beyond the scope of this volume,
and it will not be covered here; overviews of computational techniques in this area are
contained in a variety of excellent references [1–4].
Computational techniques are increasingly allowing scientists to gain new insights into
toxicological phenomena, integrate (and interpret) the results from a wide variety of
experiments, and develop more rigorous and quantitative means of assessing chemical
safety and toxicity. Moreover, these techniques can provide valuable insights before initiat-
ing expensive laboratory experiments and into phenomena not easily amenable to experi-
mental analysis, e.g., detection of highly reactive, transient, or trace-level species in
biological milieu. We believe that the unique collection of explanatory material, software,
and illustrative examples in Computational Toxicology will allow motivated readers to
participate in this exciting field and undertake a diversity of realistic problems of interest.
We would like to express our sincere thanks to our authors whose enthusiasm and
diverse contributions have made this project possible.

Fort Collins, Colorado, USA Brad Reisfeld

Arthur N. Mayeno

References

1. Clark, M.M., Transport modeling for environmental engineers and scientists. 2nd ed. 2009, Hobo-
ken, N.J.: Wiley.
2. Hemond, H.F. and E.J. Fechner-Levy, Chemical fate and transport in the environment. 2nd ed.
2000, San Diego: Academic Press. xi, 433 p.
3. Logan, B.E., Environmental transport processes. 1999, New York: Wiley. xiii, 654 p.
4. Nirmalakhandan, N., Modeling tools for environmental engineers and scientists. 2002, Boca Raton,
Fla.: CRC Press. xi, 312 p.
Contents

Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

PART I TOXICOLOGICAL/PHARMACOLOGICAL ENDPOINT PREDICTION

1 Methods for Building QSARs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
James Devillers
2 Accessing and Using Chemical Databases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Nikolai Nikolov, Todor Pavlov, Jay R. Niemel€ a , and Ovanes Mekenyan
3 From QSAR to QSIIR: Searching for Enhanced Computational
Toxicology Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Hao Zhu
4 Mutagenicity, Carcinogenicity, and Other End points . . . . . . . . . . . . . . . . . . . . . . . . 67
Romualdo Benigni, Chiara Laura Battistelli, Cecilia Bossa,
Mauro Colafranceschi, and Olga Tcheremenskaia
5 Classification Models for Safe Drug Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
A.K. Madan, Sanjay Bajaj, and Harish Dureja
6 QSAR and Metabolic Assessment Tools in the Assessment of Genotoxicity . . . . . . 125
Andrew P. Worth, Silvia Lapenna, and Rositsa Serafimova

PART II BIOLOGICAL NETWORK MODELING

7 Gene Expression Networks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165

Reuben Thomas and Christopher J. Portier
8 Construction of Cell Type-Specific Logic Models of Signaling Networks
Using CellNOpt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
Melody K. Morris, Ioannis Melas, and Julio Saez-Rodriguez
9 Regulatory Networks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
Gilles Bernot, Jean-Paul Comet, and Christine Risso-de Faverney
10 Computational Reconstruction of Metabolic Networks from KEGG . . . . . . . . . . . 235
Tingting Zhou

PART III BIOMARKERS

11 Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253
Harmony Larson, Elena Chan, Sucha Sudarsanam, and Dale E. Johnson
12 Biomonitoring-based Environmental Public
Health Indicators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Andrey I. Egorov, Dafina Dalbokova, and Michal Krzyzanowski

vii
viii Contents

PART IV MODELING FOR REGULATORY PURPOSES

(RISK AND SAFETY ASSESSMENT)
13 Modeling for Regulatory Purposes (Risk and Safety Assessment). . . . . . . . . . . . . . . 297
Hisham El-Masri
14 Developmental Toxicity Prediction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
Raghuraman Venkatapathy and Nina Ching Y. Wang
15 Predictive Computational Toxicology to Support Drug Safety Assessment. . . . . . . 341
Luis G. Valerio Jr.

PART V INTEGRATED MODELING/SYSTEMS TOXICOLOGY APPROACHES

16 Developing a Practical Toxicogenomics Data Analysis System Utilizing

Open-Source Software . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
Takehiro Hirai and Naoki Kiyosawa
17 Systems Toxicology from Genes to Organs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 375
John Jack, John Wambaugh, and Imran Shah
18 Agent-Based Models of Cellular Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399
Nicola Cannata, Flavio Corradini, Emanuela Merelli, and Luca Tesei

PART VI MATHEMATICAL AND STATISTICAL BACKGROUND

19 Linear Algebra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 429
Kenneth Kuttler
20 Ordinary Differential Equations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475
Jiřı́ Lebl
21 On the Development and Validation of QSAR Models . . . . . . . . . . . . . . . . . . . . . . . 499
Paola Gramatica
22 Principal Components Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 527
Detlef Groth, Stefanie Hartmann, Sebastian Klie, and Joachim Selbig
23 Partial Least Squares Methods: Partial Least Squares Correlation
and Partial Least Square Regression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 549
Hervé Abdi and Lynne J. Williams
24 Maximum Likelihood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 581
Shuying Yang and Daniela De Angelis
25 Bayesian Inference. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 597
Frederic Y. Bois
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 637
Contributors

HERVÉ ABDI  School of Behavioral and Brain Sciences, The University of Texas
at Dallas, Richardson, TX, USA
SANJAY BAJAJ  S.V. College of Pharmacy, Patiala, India
CHIARA LAURA BATTISTELLI  Environment and Health Department, Istitituto
Superiore di Sanita’, Rome, Italy
ROMUALDO BENIGNI  Environment and Health Department, Istitituto Superiore
di Sanita’, Rome, Italy
GILLES BERNOT  I3S laboratory, UMR 6070 CNRS, University of Nice-Sophia
Antipolis, Sophia Antipolis, France
FREDERIC Y. BOIS  Technological University of Compiegne, Royallieu Research Center,
Compiegne, France; INERIS, DRC/VIVA/METO, Verneuil en Halatte, France
CECILIA BOSSA  Environment and Health Department, Istitituto Superiore di Sanita’,
Rome, Italy
NICOLA CANNATA  School of Science and Technology, University of Camerino,
Camerino, Italy
ELENA CHAN  Emiliem, Inc., San Francisco, CA, USA
MAURO COLAFRANCESCHI  Environment and Health Department, Istitituto Superiore
di Sanita’, Rome, Italy
FLAVIO CORRADINI  School of Science and Technology, University of Camerino,
Camerino, Italy
DAFINA DALBOKOVA  Consultant, Sofia, Bulgaria
DANIELA DE ANGELIS  MRC Biostatistics Unit, Institute of Public Health, University
Forvie Site, Cambridge, UK
JOHN C. DEARDEN  School of Pharmacy & Biomolecular Sciences, Liverpool John Moores
University, Liverpool, UK
JAMES DEVILLERS  CTIS, Rillieux La Pape, France
HARISH DUREJA  Department of Pharmaceutical Sciences, M. D. University,
Rohtak, India
ANDREY I. EGOROV  World Health Organization (WHO), Regional Office for Europe,
European Centre for Environment and Health (ECEH), Bonn, Germany
HISHAM EL-MASRI  Integrated Systems Toxicology Division, Systems Biology Branch,
US Environmental protection Agency, Research Triangle Park, NC, USA
CHRISTINE RISSO-DE FAVERNEY  ECOMERS laboratory, University of Nice-Sophia
Antipolis, Nice Cedex, France
PAOLA GRAMATICA  QSAR Research Unit in Environmental Chemistry and
Ecotoxicology, Theoretical and Applied Sciences, University of Insubria,
via Dunant 3, Varese, Italy
DETLEF GROTH  AG Bioinformatics, University of Potsdam, Potsdam-Golm, Germany
STEFANIE HARTMANN  AG Bioinformatics, University of Potsdam,
Potsdam-Golm, Germany

ix
x Contributors

TAKEHIRO HIRAI  Translational Medicine and Clinical Pharmacology Department,

Daiichi Sankyo Co., Ltd., Tokyo, Japan
JOHN JACK  U.S. Environmental Protection Agency, Research Triangle Park,
NC, USA
DALE E. JOHNSON  Emiliem, Inc., San Francisco, CA, USA
NAOKI KIYOSAWA  Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd.,
Fukuroi, Shizuoka, Japan
SEBASTIAN KLIE  AG Bioinformatics, University of Potsdam, Potsdam-Golm, Germany
MICHAL KRZYZANOWSKI  World Health Organization (WHO), Regional Office
for Europe, European Centre for Environment and Health (ECEH), Bonn, Germany
KENNETH KUTTLER  Department of Math, Brigham Young University, Provo,
UT, USA
SILVIA LAPENNA  Institute for Health and Consumer Protection, European
Commission–Joint Research Centre, Ispra (VA), Italy
HARMONY LARSON  Emiliem, Inc., San Francisco, CA, USA
JIŘÍ LEBL  Department of Mathematics, University of Wisconsin-Madison, Madison,
WI, USA
A.K. MADAN  Department of Pharmaceutical Sciences, Pt. B.D. Sharma University
of Health Sciences, Rohtak, India
OVANES MEKENYAN  Laboratory of Mathematical Chemistry, University ‘Prof. Asses
Zlatarov’, Bourgas, Bulgaria
IOANNIS MELAS  European Bioinformatics Institute (EMBL-EBI), Cambridge, UK;
National Technical University of Athens, Athens, Greece
EMANUELA MERELLI  School of Science and Technology, University of Camerino,
Camerino, Italy
MELODY K. MORRIS  Center for Cell Decision Processes Massachusetts Institute of
Technology and Harvard Medical School, Cambridge, MA, USA;
Department of Biological Engineering, Massachusetts Institute of Technology,
Cambridge, MA, USA
JAY R. NIEMELÄ  National Food Institute Technical University of Denmark,
Soeborg, Denmark
NIKOLAI NIKOLOV  National Food Institute Technical University of Denmark,
Soeborg, Denmark
TODOR PAVLOV  Laboratory of Mathematical Chemistry, University ‘Prof. Asses
Zlatarov’, Bourgas, Bulgaria
CHRISTOPHER J. PORTIER  National Center for Environmental Health
and Agency for Toxic Substances and Disease Registry Centers for Disease
and Prevention, Atlanta, GA, USA
JULIO SAEZ-RODRIGUEZ  European Bioinformatics Institute (EMBL-EBI),
Cambridge, UK; Genome Biology Unit, European Molecular Biology Laboratory
(EMBL), Heidelberg, Germany
JOACHIM SELBIG  AG Bioinformatics, University of Potsdam, Potsdam-Golm, Germany
ROSITSA SERAFIMOVA  Institute for Health and Consumer Protection, European
Commission–Joint Research Centre, Ispra (VA), Italy
IMRAN SHAH  U.S. Environmental Protection Agency, Research Triangle Park,
NC, USA
 Contributors xi

SUCHA SUDARSANAM  Emiliem, Inc., San Francisco, CA, USA

OLGA TCHEREMENSKAIA  Environment and Health Department, Istitituto Superiore
di Sanita’, Rome, Italy
LUCA TESEI  School of Science and Technology, University of Camerino, Camerino, Italy
REUBEN THOMAS  Division of Environmental Health Sciences,
University of California, Berkeley, CA, USA
LUIS G. VALERIO JR  Office of Pharmaceutical Science, Center for Drug Evaluation
and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA
RAGHURAMAN VENKATAPATHY  Pegasus Technical Services, Inc., Cincinnati, OH, USA
JOHN WAMBAUGH  U.S. Environmental Protection Agency, Research Triangle Park,
NC, USA
NINA CHING Y. WANG  National Center for Environmental Assessment,
U. S. Environmental Protection Agency, Office of Research and Development,
Cincinnati, OH, USA
LYNNE J. WILLIAMS  Kunin-Lunenfeld Applied Research Unit, Rotman Research
Institute at Baycrest, Toronto, Canada
ANDREW P. WORTH  Institute for Health and Consumer Protection, European
Commission–Joint Research Centre, Ispra (VA), Italy
SHUYING YANG  GlaxoSmithKline Services Unlimited, Brentford, Middlesex, UK
TINGTING ZHOU  Laboratory of Molecular Immunology, Institute of Basic Medical
Sciences, Beijing, People’s Republic of China
HAO ZHU  Department of Chemistry,The Rutgers Center for Computational and
Integrative Biology Rutgers University 315 Penn St. Camden, NJ 08102 University
of North Carolina Chapel Hill, NC, USA
 Part I

Toxicological/Pharmacological Endpoint Prediction

 Chapter 1

Methods for Building QSARs

James Devillers

Abstract
Structure–activity relationship (SAR) and quantitative structure–activity relationship (QSAR) models are
increasingly used in toxicology, ecotoxicology, and pharmacology for predicting the activity of the mole-
cules from their physicochemical properties and/or their structural characteristics. However, the design of
such models has many traps for unwary practitioners. Consequently, the purpose of this chapter is to give a
practical guide for the computation of SAR and QSAR models, point out problems that may be encoun-
tered, and suggest ways of solving them. Attempts are also made to see how these models can be validated
and interpreted.

Key words: QSAR, SAR, Linear model, Nonlinear model, Validation

1. Introduction

All branches of research benefit from the use of computers, even

though no increase of memory size or processor speed will compen-
sate for lack of original ideas, analytical mind, or specialized exper-
tise. Nevertheless, the impact of computers in structure–activity
relationship (SAR) and quantitative structure–activity relationship
(QSAR) that try to relate the activity of a set of molecules to their
chemical structures has been tremendous. Only based on empirical
relationships in the second part of the nineteenth century (1–3), the
QSARs were mathematically formalized in the 1930s (4) and their
acceptance, as a discipline in its own right, was definitively acquired
in the early 1960s from the seminal works of Hansch and Fujita (5,
6). Since then a huge number of models have been designed for the
prediction of various biological activities of interest. With the
increase of computational power, it has been possible to calculate
collections of molecular descriptors to encode more and more larger
sets of molecules for which biological data were available and also, to

Brad Reisfeld and Arthur N. Mayeno (eds.), Computational Toxicology: Volume II, Methods in Molecular Biology, vol. 930,
DOI 10.1007/978-1-62703-059-5_1, # Springer Science+Business Media, LLC 2013

3
4 J. Devillers

be not limited in the choice of a statistical method to derive linear

and nonlinear SARs. However independently of their characteristics
and complexity, the design of SAR and QSAR models is under-
pinned by the respect of the same basic principles. In this context,
the goal of this chapter is to provide a practical guide to the design of
SAR and QSAR models and consequently, to underline the com-
mon pitfalls to avoid in the building of such models. It is expected
that this chapter will prove useful to those who are unfamiliar with
the discipline. Intended first to people interested in the design of
models in toxicology and ecotoxicology, most of the concepts and
remarks discussed in this chapter remain true regarding the design
of QSAR in pharmacology as well as the computation of structure–
property relationships called QSPRs.
The chapter is set out in the same order in which an SAR or a
QSAR model is derived starting with the selection of the biological
data for the endpoint of interest, description of the molecules,
computation of the model from a statistical tool, evaluation of
the model, estimation of its prediction performances, and last its
interpretation.

2. Biological Data

A well-defined endpoint is critical for the design of an accurate

QSAR model. Thus, for deriving a structure–toxicity model, it is
required to select toxicity data obtained from standardized proce-
dures. LD50 values (i.e., doses of chemicals at which 50% of the test
organisms die) have to be preferentially used for the determination
of the acute toxicity of chemicals to rodents due to their better
statistical and toxicological significance. The LD50 values are influ-
enced by the species, strain, gender, and physiological conditions of
the animals as well as the experimental conditions in which the
laboratory assay is performed. Thus, for example, Gaines (7, 8)
using adult Sherman strain rats under strictly the same experimental
conditions showed that most of the pesticides tested by the oral
route were more toxic to female than to male rats. This is illustrated
in Table 1 where the difference of sensibility between male and
female rats is indicated by the fact that the confidence limits of the
LD50 values for each of these pesticides do not overlap between the
sexes. The greater chemical metabolizing activity of liver micro-
somes in male rat (9) probably accounts for many of the sex-related
differences in acute toxicity which are observed in this species. It is
noteworthy that from the Gaines data, a QSAR model was proposed
by Devillers (10) for predicting the acute toxicity of organophos-
phorus pesticides to rats that included the gender of the organisms
in the modeling process in addition to the molecular descriptors.
 1 Methods for Building QSARs 5

Table 1
Acute oral toxicity of some pesticides in male and female
rats (7, 8)

LD50 (mg/kg) LD50 (mg/kg)

Name CAS RN in males in females
Coumaphos 56-72-4 41 (34–50)a 16 (14–17)
Endosulfan 115-29-7 43 (41–46) 18 (15–21)
Endrin 72-20-8 17.8 (14.7–21.5) 7.5 (6.8–8.3)
EPN 2104-64-5 36 (33–40) 7.7 (6.9–8.6)
Isodrin 465-73-6 15.5 (12.7–19.1) 7 (6–8.1)
Methyl parathion 298-00-0 14 (12–17) 24 (22–28)
Mevinphos 298-01-1 6.1 (5.2–7.1) 3.7 (3–4.5)
Parathion 56-38-2 13 (10–17) 3.6 (3.2–4)
Schradan 152-16-9 9.1 (8.1–10.2) 42 (32–55)
a
Confidence limits

Use of his/her own experimental toxicity data for deriving a

QSAR model minimizes the biases. However, in practice, this
situation is not usual and generally the biological data are retrieved
from publications, databases, and/or the Internet (11). When it is
not possible to obtain all the desired data from one source, it is
necessary to verify their compatibility.
Very often, the biological data need to be transformed before
used for deriving a QSAR model. Thus, for example, the LD50
values of chemicals have to be expressed on a molar basis to be
structurally comparable. In addition, they have to be converted into
a logarithmic scale to avoid statistical problems when classical sta-
tistical methods, such as regression analysis, are used to derive the
models. By convention, negative logarithms are preferred to obtain
larger values for the more active chemicals. The biological data set
after its logarithmic transformation should ideally span several
orders of magnitude to be safely used for deriving a QSAR model.
It is worth noting that if the LD50 values have heterogeneous
or dubious origins, it is needed to transform them into categorical
data. The choice of the threshold limits and number of categories
is problem dependent. Some toxicological activities, such as carci-
nogenicity, are basically expressed in a Boolean manner (i.e.,
carcinogenic/noncarcinogenic) and are modeled as such (12–14).
From a semantic point of view, the structure–activity models
computed from categorical response data are called SAR models.
They are derived from specific statistical methods (see Subhead-
ing 4). It is important to note that the use of imbalanced data sets
affects the performances of the models (15, 16). This was recently
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