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 Medical Image Analysis and
­Informatics: Computer-Aided
Diagnosis and Therapy
 Medical Image Analysis and
­Informatics: Computer-Aided
Diagnosis and Therapy

Edited by
Paulo Mazzoncini de Azevedo-Marques
Arianna Mencattini
Marcello Salmeri
Rangaraj M. Rangayyan
MATLAB ® and Simulink® are trademarks of the MathWorks, Inc. and are used with permission. The MathWorks does not war-
rant the accuracy of the text or exercises in this book. This book’s use or discussion of MATLAB ® and Simulink® software or
related products does not constitute endorsement or sponsorship by the MathWorks of a particular pedagogical approach or
particular use of the MATLAB ® and Simulink® software.

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© 2018 by Taylor & Francis Group, LLC

CRC Press is an imprint of Taylor & Francis Group, an Informa business

No claim to original U.S. Government works

Printed on acid-free paper

International Standard Book Number-13: 978-1-4987-5319-7 (Hardback)

This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to pub-
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 We dedicate this book
with gratitude and admiration
to medical specialists and clinical researchers
who collaborate with engineers and scientists
on computer-aided diagnosis and therapy
for improved health care.

Paulo, Arianna, Marcello, and Raj

 Contents

Foreword on CAD: Its Past, Present, and Future..................................................... ix

Kunio Doi
Preface...................................................................................................................... xv
Acknowledgment .. ................................................................................................... xxi
Editors.. ..................................................................................................................xxiii
Contributors........................................................................................................... xxv

1 Segmentation and Characterization of White Matter Lesions in FLAIR

Magnetic Resonance Imaging. . ...........................................................................1
Brittany Reiche, Jesse Knight, Alan R. Moody, April Khademi
2 Computer-Aided Diagnosis with Retinal Fundus Images.............................. 29
Yuji Hatanaka, Hiroshi Fujita
3 Computer-Aided Diagnosis of Retinopathy of Prematurity in Retinal
Fundus Images.. ................................................................................................ 57
Faraz Oloumi, Rangaraj M. Rangayyan, Anna L. Ells
4 Automated OCT Segmentation for Images with DME................................... 85
Sohini Roychowdhury, Dara D. Koozekanani, Michael Reinsbach, Keshab K. Parhi
5 Computer-Aided Diagnosis with Dental Images........................................... 103
Chisako Muramatsu, Takeshi Hara, Tatsuro Hayashi, Akitoshi Katsumata, Hiroshi Fujita
6 CAD Tool and Telemedicine for Burns..........................................................129
Begoña Acha-Piñero, José-Antonio Pérez-Carrasco, Carmen Serrano-Gotarredona
7 CAD of Cardiovascular Diseases. . .................................................................. 145
Marco A. Gutierrez, Marina S. Rebelo, Ramon A. Moreno, Anderson G. Santiago,
Maysa M. G. Macedo
8 Realistic Lesion Insertion for Medical Data Augmentation.......................... 187
Aria Pezeshk, Nicholas Petrick, Berkman Sahiner
9 Diffuse Lung Diseases (Emphysema, Airway and Interstitial Lung Diseases)......203
Marcel Koenigkam Santos, Oliver Weinheimer

vii
viii Contents

10 Computerized Detection of Bilateral Asymmetry.........................................219

Arianna Mencattini, Paola Casti, Marcello Salmeri, Rangaraj M. Rangayyan
11 Computer-Aided Diagnosis of Breast Cancer with Tomosynthesis
Imaging .. ..........................................................................................................241
Heang-Ping Chan, Ravi K. Samala, Lubomir M. Hadjiiski, Jun Wei
12 Computer-Aided Diagnosis of Spinal Abnormalities................................... 269
Marcello H. Nogueira-Barbosa, Paulo Mazzoncini de Azevedo-Marques
13 CAD of GI Diseases with Capsule Endoscopy.............................................. 285
Yixuan Yuan, Max Q.-H. Meng
14 Texture-Based Computer-Aided Classification of Focal Liver Diseases
using Ultrasound Images............................................................................... 303
Jitendra Virmani, Vinod Kumar
15 CAD of Dermatological Ulcers (Computational Aspects of CAD for
Image Analysis of Foot and Leg Dermatological Lesions).. .......................... 323
Marco Andrey Cipriani Frade, Guilherme Ferreira Caetano, É derson Dorileo
16 In Vivo Bone Imaging with Micro-Computed Tomography. . ........................335
Steven K. Boyd, Pierre-Yves Lagacé
17 Augmented Statistical Shape Modeling for Orthopedic Surgery and
Rehabilitation . . ............................................................................................... 369
Bhushan Borotikar, Tinashe Mutsvangwa, Valérie Burdin, Enjie Ghorbel,
Mathieu Lempereur, Sylvain Brochard, Eric Stindel, Christian Roux
18 Disease-Inspired Feature Design for Computer-Aided Diagnosis of
Breast Cancer Digital Pathology Images....................................................... 427
Jesse Knight, April Khademi
19 Medical Microwave Imaging and Analysis....................................................451
Rohit Chandra, Ilangko Balasingham, Huiyuan Zhou, Ram M. Narayanan
20 Making Content-Based Medical Image Retrieval Systems for
Computer-Aided Diagnosis: From Theory to Application........................... 467
Agma Juci Machado Traina, Marcos Vinícius Naves Bedo, Lucio Fernandes Dutra
Santos, Luiz Olmes Carvalho, Glauco Vítor Pedrosa, Alceu Ferraz Costa, Caetano Traina Jr.
21 Health Informatics for Research Applications of CAD.................................491
Thomas M. Deserno, Peter L. Reichertz

Concluding Remarks. . ........................................................................................... 505

Paulo Mazzoncini de Azevedo-Marques, Arianna Mencattini, Marcello Salmeri,
Rangaraj Mandayam Rangayyan
Index. . ..................................................................................................................... 509
 Foreword on CAD:
Its Past, Present, and Future

Computer-aided diagnosis (CAD) has become a routine clinical procedure for detection of breast cancer
on mammograms at many clinics and medical centers in the United States. With CAD, radiologists
use the computer output as a “ second opinion” in making their final decisions. Of the total number
of approximately 38 million mammographic examinations annually in the United States, it has been
estimated that about 80% have been studied with use of CAD. It is likely that CAD is beginning to be
applied widely in the detection and differential diagnosis of many different types of abnormalities in
medical images obtained in various examinations by use of different imaging modalities, including
projection radiography, computed tomography (CT), magnetic resonance imaging (MRI), ultrasonog-
raphy, nuclear medicine imaging, and other optical imaging systems. In fact, CAD has become one of
the major research subjects in medical imaging, diagnostic radiology, and medical physics. Although
early attempts at computerized analysis of medical images were made in the 1960s, serious and system-
atic investigations on CAD began in the 1980s with a fundamental change in the concept for utilization
of the computer output, from automated computer diagnosis to computer-aided diagnosis.
Large-scale and systematic research on and development of various CAD schemes was begun by us in
the early 1980s at the Kurt Rossmann Laboratories for Radiologic Image Research in the Department of
Radiology at the University of Chicago. Prior to that time, we had been engaged in basic research related
to the effects of digital images on radiologic diagnosis, and many investigators had become involved
in research and development of a picture archiving and communication system (PACS). Although it
seemed that PACS would be useful in the management of radiologic images in radiology departments
and might be beneficial economically to hospitals, it looked unlikely at that time that PACS would bring
a significant clinical benefit to radiologists. Therefore, we thought that a major benefit of digital images
must be realized in radiologists’ daily work of image reading and radiologic diagnosis. Thus, we came to
the concept of computer-aided diagnosis.
In the 1980s, the concept of automated diagnosis or automated computer diagnosis was already known
from studies performed in the 1960s and 1970s. At that time, it was assumed that computers could
replace radiologists in detecting abnormalities, because computers and machines are better at perform-
ing certain tasks than human beings. These early attempts were not successful because computers were
not powerful enough, advanced image processing techniques were not available, and digital images were
not easily accessible. However, a serious flaw was an excessively high expectation from computers. Thus,
it appeared to be extremely difficult at that time to carry out a computer analysis of medical images. It
was uncertain whether the development of CAD schemes would be successful or would fail. Therefore,
we selected research subjects related to cardiovascular diseases, lung cancer, and breast cancer, includ-
ing for detection and/or quantitative analysis of lesions involved in vascular imaging, as studied by H.
Fujita and K.R. Hoffmann; detection of lung nodules in chest radiographs by M.L. Giger; and detection
of clustered microcalcifications in mammograms by H.P. Chan.

ix
x Foreword on CAD: Its Past, Present, and Future

Our efforts concerning research and development of CAD for detection of lesions in medical images
have been based on the understanding of processes that are involved in image readings by radiologists.
This strategy appeared logical and straightforward because radiologists carry out very complex and
difficult tasks of image reading and radiologic diagnosis. Therefore, we considered that computer algo-
rithms should be developed based on the understanding of image readings, such as how radiologists can
detect certain lesions, why they may miss some abnormalities, and how they can distinguish between
benign and malignant lesions.
Regarding CAD research on lung cancer, we attempted in the mid-1980s to develop a computerized
scheme for detection of lung nodules on chest radiographs. The visual detection of lung nodules is
well-known as a difficult task for radiologists, who may miss up to 30% of the nodules because of the
overlap of normal anatomic structures with nodules, i.e., the normal background in chest images tends
to camouflage nodules. Therefore, the normal background structures in chest images could become a
large obstacle in the detection of nodules, even by computer. Thus, the first step in the computerized
scheme for detection of lung nodules in chest images would need to be the removal or suppression of
background structures in chest radiographs. A method for suppressing the background structures is the
difference-image technique, in which the difference between a nodule-enhanced image and a nodule-
suppressed image is obtained. This difference-image technique, which may be considered a general-
ization of an edge enhancement technique, has been useful in enhancing lesions and suppressing the
background not only for nodules in chest images, but also for microcalcifications and masses in mam-
mograms, and for lung nodules in CT.
At the Rossmann Laboratories in the mid-1980s, we had already developed basic schemes for the
detection of lung nodules in chest images and for the detection of clustered microcalcifications in mam-
mograms. Although the sensitivities of these schemes for detection of lesions were relatively high, the
number of false positives was very large. It was quite uncertain whether the output of these comput-
erized schemes could be used by radiologists in their clinical work. For example, the average num-
ber of false positives obtained by computer was four per mammogram in the detection of clustered
­microcalcifications, although the sensitivity was about 85%. However, in order to examine the possibil-
ity of practical uses of CAD in clinical situations, we carried out an observer performance study without
and with computer output. To our surprise, radiologists’ performance in detecting clustered microcal-
cifications was improved significantly when the computer output was available. A paper was published
in 1990 by H.P. Chan providing the first scientific evidence that CAD could be useful in improving
radiologists’ performance in the detection of a lesion. Many investigators have reported similar findings
on the usefulness of CAD in detecting various lesions, namely, masses in mammograms, lung nodules
and interstitial opacities in chest radiographs, lung nodules in CT, intracranial aneurysms in magnetic
resonance angiography (MRA), and polyps in CT colonography.
The two concepts of automated computer diagnosis and computer-aided diagnosis clearly exist even
at present. Therefore, it may be useful to understand the common features and also the differences
between CAD and automated computer diagnosis. The common approach to both CAD and automated
computer diagnosis is that digital medical images are analyzed quantitatively by computers. Therefore,
the development of computer algorithms is required for both CAD and computer diagnosis. A major
difference between CAD and computer diagnosis is the way in which the computer output is utilized for
the diagnosis. With CAD, radiologists use the computer output as a “ second opinion,” and radiologists
make the final decisions. Therefore, for some clinical cases in which radiologists are confident about
their judgments, radiologists may agree with the computer output, or they may disagree and then dis-
regard the computer. However, for cases in which radiologists are less confident, it is expected that the
final decision can be improved by use of the computer output. This improvement is possible, of course,
only when the computer result is correct. However, the performance level of the computer does not have
to be equal to or higher than that of radiologists. With CAD, the potential gain is due to the synergistic
effect obtained by combining the radiologist’ s competence with the computer’ s capability, and thus the
current CAD scheme has become widely used in practical clinical situations.
Foreword on CAD: Its Past, Present, and Future xi

With automated computer diagnosis, however, the performance level of the computer output is
required to be very high. For example, if the sensitivity for detection of lesions by computer were lower
than the average sensitivity of physicians, it would be difficult to justify the use of automated computer
diagnosis. Therefore, high sensitivity and high specificity by computer would be required for implement-
ing automated computer diagnosis. This requirement is extremely difficult for researchers to achieve in
developing computer algorithms for detection of abnormalities on medical images.
The majority of papers related to CAD research presented at major meetings such as those of the
RSNA, AAPM, SPIE, and CARS from 1986 to 2015 were concerned with three organs– chest, breast,
and colon– but other organs such as brain, liver, and skeletal and vascular systems were also subjected
to CAD research. The detection of cancer in the breast, lung, and colon has been subjected to screening
examinations. The detection of only a small number of suspicious lesions by radiologists is considered
both difficult and time-consuming because a large fraction of these examinations are normal. Therefore,
it appears reasonable that the initial phase of CAD in clinical situations has begun for these screening
examinations. In mammography, investigators have reported results from prospective studies on large
numbers of patients regarding the effect of CAD on the detection rate of breast cancer. Although there
is a large variation in the results, it is important to note that all of these studies indicated an increase in
the detection rates of breast cancer with use of CAD.
In order to assist radiologists in their differential diagnosis, in addition to providing the likelihood of
malignancy as the output of CAD, it would be useful to provide a set of benign and malignant images
that are similar to an unknown new case under study; this may be achieved using methods of content-
based image retrieval (CBIR). If the new case were considered by a radiologist to be very similar to one
or more benign (or malignant) images, he/she would be more confident in deciding that the new case
was benign (or malignant). Therefore, similar images may be employed as a supplement to the computed
likelihood of malignancy in implementing CAD for a differential diagnosis.
The usefulness of similar images has been demonstrated in an observer performance study in which
the receiver operating characteristic (ROC) curve in the distinction between benign and malignant
microcalcifications in mammograms was improved. Similar findings have been reported for the dis-
tinction between benign and malignant masses, and also between benign and malignant nodules in
thoracic CT. There are two important issues related to the use of similar images in clinical situations.
One is the need for a unique database that includes a large number of images, which can be used as being
similar to those of many unknown new cases, and another is the need for a sensitive tool for finding
images similar to an unknown case.
At present, the majority of clinical images in PACS have not been used for clinical purposes, except
for images of the same patients for comparison of a current image with previous images. Therefore, it
would not be an overstatement to say that the vast majority of images in PACS are currently “ sleep-
ing” and need to be awakened in the future for daily use in clinical situations. It would be possible to
search for and retrieve very similar cases with similar images from PACS. Recent studies indicated that
the similarity of a pair of lung nodules in CT and of lesions in mammograms may be quantified by a
psychophysical measure which can be obtained by use of an artificial neural network trained with the
corresponding image features and with subjective similarity ratings given by a group of radiologists.
However, further investigations are required for examining the usefulness of this type of new tool for
searching similar images in PACS.
It is likely that some CAD schemes will be included together with software for image processing in
workstations associated with imaging modalities such as digital mammography, CT, and MRI. However,
many other CAD schemes will be assembled as packages and will be implemented as a part of PACS. For
example, the package for chest CAD may include the computerized detection of lung nodules, intersti-
tial opacities, cardiomegaly, vertebral fractures, and interval changes in chest radiographs, as well as the
computerized classification of benign and malignant nodules. All of the chest images taken for whatever
purpose will be subjected to a computerized search for many different types of abnormalities included
in the CAD package, and, thus, potential sites of lesions, together with relevant information such as the
xii Foreword on CAD: Its Past, Present, and Future

likelihood of malignancy and the probability of a certain disease, may be displayed on the workstation.
For such a package to be used in clinical situations, it is important to reduce the number of false posi-
tives as much as possible so that radiologists will not be distracted by an excessive number of these, but
will be prompted only by clinically significant abnormalities.
Radiologists may use this type of CAD package in the workstation for three different reading meth-
ods. One is first to read images without the computer output, and then to request a display of the com-
puter output before making the final decision; this “ second-read” mode has been the condition that the
Food and Drug Administration (FDA) in the United States has required for approval of a CAD system as
a medical device. If radiologists keep their initial findings in some manner, this second-read mode may
prevent a detrimental effect of the computer output on radiologists’ initial diagnosis, such as incorrectly
dismissing a subtle lesion because of the absence of a computer output, although radiologists were very
suspicious about this lesion initially. However, this second-read mode would increase the time required
for radiologists’ image reading, which is undesirable.
Another mode is to display the computer output first and then to have the final decision made by a
radiologist. With this “concurrent” mode, it is likely that radiologists can reduce the reading time for
image interpretations, but it is uncertain whether they may miss some lesions when no computer output
was shown, due to computer false negatives. This negative effect can be reduced if the sensitivity in the
detection of abnormalities is at a very high level, which may be possible with a package of a number of dif-
ferent, but complementary CAD schemes. For example, although two CAD schemes may miss some lung
nodules and other interstitial opacities on chest radiographs, it is possible that the temporal subtraction
images obtained from the current and previous chest images demonstrate interval changes clearly because
the temporal subtraction technique is very sensitive to subtle changes between the two images. This would
be one of the potential advantages of packaging of a number of CAD schemes in the PACS environment.
The third method is called a “ first-read” mode, in which radiologists would be required to examine
only the locations marked by the computer. With this first-read mode, the sensitivity of the computer
software must be extremely high, and if the number of false positives is not very high, the reading time
may be reduced substantially. It is possible that a certain type of radiologic examination requiring a
long reading time could be implemented by the concurrent-read mode or the first-read mode due to
economic and clinical reasons, such as a shortage of radiologist manpower. However, this would depend
on the level of performance by the computer algorithm, and, at present, it is difficult to predict what level
of computer performance would make this possible. Computer-aided diagnosis has made a remarkable
progress during the last three decades by numerous investigators around the world, including those
listed in the footnote* and researchers at the University of Chicago. It is likely in the future that the
concept, methods, techniques, and procedures related to CAD and quantitative image analysis would
be applied to and used in many other related fields, including medical optical imaging systems and
devices, radiation therapy, surgery, and pathology, as well as radiomics and imaging genomics in radi-
ology and radiation oncology. In the future, the benefits of CAD and quantitation of image data need
to be realized in conjunction with progress in other fields including informatics, CBIR, PACS, hospital

* Faculty, research staff, students, and international visitors who participated in research and development of CAD schemes
in the Rossmann Laboratory over the last three decades have moved to academic institutions worldwide and continue to
contribute to the progress in this field. They are H. P. Chan, University of Michigan; K.R. Hoffmann, SUNY Buffalo; H.
Yoshida, MGH; R. M. Nishikawa, K. T. Bae, University of Pittsburgh; N. Alperin, University of Miami; F. F. Yin, Duke
University; K. Suzuki, Illinois Institute of Technology; L. Fencil, Yale University; P. M. Azevedo-Marques, University
of Sã o Paulo, Brazil; Q. Li, Shanghai Advanced Research Institute, China; U. Bick, Charite University Clinic, Germany;
M. Fiebich, University of Applied Sciences, Germany; B. van Ginneken, Radbound University, The Netherlands; P.
Tahoces, University of Santiago de Compostella, Spain; H. Fujita, T. Hara, C. Muramatsu, Gifu University, Japan; S.
Sanada, R. Tanaka, Kanazawa University, Japan; S. Katsuragawa, Teikyo University, Japan; J. Morishita, H. Arimura,
Kyushu University, Japan; J. Shiraishi, Y. Uchiyama, Kumamoto University, Japan; T. Ishida, Osaka University, Japan; K.
Ashizawa, Nagasaki University, Japan; K. Chida, Tohoku University, Japan; T. Ogura, M. Shimosegawa, H. Nagashima,
Gunma Prefectural College of Health Sciences, Japan.
Foreword on CAD: Its Past, Present, and Future xiii

information systems (HIS), and radiology information systems (RIS). Due to the recent development of
new artificial intelligence technologies such as a deep learning neural network, the performance of the
computer algorithm may be improved substantially in the future, but will be carefully examined for
practical uses in complex clinical situations. Computer-aided diagnosis is still in its infancy in terms
of the development of its full potential for applications to many different types of lesions obtained with
various diagnostic modalities.

Kunio Doi, PhD

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