1999 146 Computer-aided Diagnosis Applied to US of Solid Breast Nodules by Using Neural Networks
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Computer ApplicationsComputer-aided Diagnosis Applied to US of Solid Breast Nodules by Using Neural Networks1PURPOSE:To increase the capabilities of ultrasonographic(US)technology for the differential diagnosis of solid breast tumors by using a neural network.MATERIALS AND METHODS:One hundred forty US images of solid breast nodules were evaluated.When a sonogram was obtained,an analog video signal from the VCR output of the scanner was transmitted to a notebook computer.A frame grabber connected to the printer port of the computer was then used to digitize the data.The suspicious tumor region on the digitized US image was manually selected.The texture information of the subimage was extracted,and a neural network classifier with autocorrelation features was used to classify the tumor as benign or malignant.In this experiment,140pathologically proved tumors(52malignant and 88benign tumors)were sampled with k-fold cross-validation(kϭ10)to evaluate the performance with receiver operating characteristic curves.RESULTS:The accuracy of neural networks for classifying malignancies was95.0% (133of140tumors),the sensitivity was98%(51of52),the specificity was93%(82 of88),the positive predictive value was89%(51of57),and the negative predictive value was99%(82of83).CONCLUSION:This system differentiated solid breast nodules with relatively high accuracy and helped inexperienced operators to avoid misdiagnoses.Because the neural network is trainable,it could be optimized if a larger set of tumor images is supplied.Breast cancer ranks first in the causes of cancer deaths among women in developed countries and is second to cervical cancer in developing countries(1).The best way to reduce deaths due to breast cancer is to treat the disease at an earlier stage.Earlier treatment requires early diagnosis,and early diagnosis requires an accurate and reliable diagnostic procedure that allows physicians to differentiate benign breast tumors from malignant ones.Current procedures for detecting and diagnosing breast cancers,however,illustrate the difficulty in maximizing both sensitivity and specificity.Although the smaller hospitals use conventional ultrasonographic(US)equipment to obtain medical images quickly,estimates of the accuracy of US diagnostic methods are controversial,and the role of US in current practice is not yet defined(2,3).One of the important reasons for this controversy is the considerable overlap of benign and malignant findings on US images;interpretation is subjective and depends on the operator.The US examination described by Stavros et al(4)is much more extensive than the usual examinations performed at most breast imaging centers.In their study,Stavros et al(4) found that the sensitivity of breast US for malignancy was98.4%(123of125findings),the specificity was67.8%(424of625),the overall accuracy was72.9%(547of750),the positive predictive value was38.0%(123of324),and the negative predictive value was99.5%(424 of426).However,these improved diagnostic results were achieved by experienced radiologists.In practice,many invasive diagnostic procedures are still required in most cases.Most of these procedures are avoidable because the rate of positive findings at biopsy for cancer is low—between10%and31%(5–7).To overcome the aforementioned407shortcomings of US and to fully expand the capability of US,only an efficient computerized model offers objective evi-dence and avoids interobserver varia-tions;therefore,an optimal and stable high diagnostic rate can be achieved by using such a model.Both mammography(8–11)and US (12)can be used to detect and classify breast tumors.Although mammography can be used to visualize nonpalpable and small tumors,US is a convenient and safe tool to use in the classification of tumors, especially palpable tumors.Garra et al (13)suggest that analysis of US image texture is a simple means of markedly reducing the number of biopsies per-formed for benign lesions.Garra et al(13) used a co-occurrence matrix and the lin-ear Bayesian classifier.Neural network techniques have been applied to detect microcalcifications and have even been applied to distinguish benign and malig-nant microcalcifications on digital mam-mographic images(9–11).Moreover, Choong et al(14)used neural networks to make prognoses for women with breast cancer.The multilayer feed-forward neural net-work can be used to extract higher-order statistics by adding one or more hidden layers.This model has become extremely popular in terms of classification and prediction.The powerful error back-propagation algorithm proposed by Rumelhart el al(15)and Hirose et al(16) is the most widely used algorithm for multilayer feed-forward neural networks. We used this neural network model as a classifier to determine whether the breast tumors were benign or malignant.The diagnostic model proposed herein can exploit the nonlinear property of the learning algorithm of the neural network to classify the US images of the breast more accurately.The multilayer feed-forward neural network is a reliable choice for the proposed model because it trains well and computes efficiently. MATERIALS AND METHODSIn general,a physician can easily identify a tumor on a US image by the shape of the tumor and by the contrast of internal echoes,but the computer cannot easily segment a tumor from a digitized image. However,if a physician has already iden-tified the tumor,a computer can be used to diagnose the tumor with information about intensity variation and texture on the image.In this study,a physician (D.R.C.)first extracted the subimage of the region of interest,and then the com-puter was used to analyze the subimageby using the information about intensityvariation and texture to make a differen-tial diagnosis.Data AcquisitionThe US image database contained140images of pathologically proved tumors:benign breast tumors from88patientsand carcinomas from52patients(tumorFigure1.A,Transverse digital US image depicts a malignant tumor,with a resolution of736ϫ556pixels.Note that there are58ϫ58ϭ3,364pixels in a1ϫ1-cm rectangle.B,The region-of-interest rectangle is approximately3.1ϫ1.5cm and is captured with a resolution of 179ϫ88pixels.ROIϭregion ofinterest.a. b.Figure 2.Typical transverse US region-of-interest subimages in the breast depict(a)abenign lesion(arrows)and(b)a malignantlesion(arrows).TABLE1Mean,SD,and Mean Difference between Autocorrelation Coefficients for Malignant and Benign TumorsAutocorrelationAutocorrelation Coefficientsfor Malignant TumorsAutocorrelation Coefficientsfor Benign TumorsMeanDifferenceMean SD Mean SDAЈ(1,0)0.9660.0120.9580.0160.008 AЈ(2,0)0.9160.0270.9010.0330.015 AЈ(3,0)0.8750.0380.8570.0430.018 AЈ(4,0)0.8480.0450.8270.0500.021 AЈ(0,1)0.9150.0210.8610.0370.054 AЈ(1,1)0.8960.0270.8390.0400.057 AЈ(2,1)0.8650.0360.8050.0450.060 AЈ(3,1)0.8380.0420.7760.0490.062 AЈ(4,1)0.8180.0470.7550.0520.064 AЈ(0,2)0.8180.0390.7280.0570.091 AЈ(1,2)0.8120.0410.7200.0560.092 AЈ(2,2)0.8020.0440.7090.0560.093 AЈ(3,2)0.7920.0470.6980.0560.094 AЈ(4,2)0.7820.0500.6870.0560.095 AЈ(0,3)0.7690.0440.6560.0620.113 AЈ(1,3)0.7660.0450.6510.0600.115 AЈ(2,3)0.7620.0460.6460.0580.117 AЈ(3,3)0.7570.0480.6400.0570.118 AЈ(4,3)0.7520.0500.6340.0570.118 AЈ(0,4)0.7490.0450.6210.0620.128 AЈ(1,4)0.7460.0450.6160.0600.130 AЈ(2,4)0.7410.0470.6100.0580.131 AЈ(3,4)0.7370.0480.6050.0570.132 AЈ(4,4)0.7320.0490.6000.0560.132408•Radiology•November1999Chen et alsize,Ͼ1cm in all patients).The database contained only one image from each patient.The US images that depicted the largest diameter of the tumor were cap-tured.The images were collected from January 1,1997,to May 31,1998,and the patients’ages ranged from 18to was performed by using an Aloka SSD 1200scanner (Tokyo,Japan)and a 7.5-MHz linear transducer with freeze-frame capability.No acoustic standoff pad was used with any of the patients.The US gain setting remained unchanged throughout the entire study,except for changes made to obtain the best view.The following description explains how digital US images were obtained.When a sonogram was obtained,an analog video signal was transmitted from the VCR output of the scanner to a notebook computer.The data were then digitized by means of a Video CATcher frame grab-ber (Top Solution Technology;Taipei,Tai-wan,Republic of China)that was con-nected to the printer port of the computer.The capturing resolutions of the portable computer and the external frame grabber was 736ϫ566pixels for a National Television Systems Committee video-screen picture.We used the ProImagesoftware package from Prolab (version 2.0;Taipei,Taiwan,Republic of China),which was bundled with the frame grab-ber,to capture the real-time digital image.The monochrome US image was quan-tized to 8bits (ie,256gray levels).The subimage of the region of interest was manually selected by using the ProImage (Prolab)package.That is,the software package was used to capture the full im-age from the US scanner and to select the region-of-interest subimage manually.The region-of-interest subimage was then saved as a file for later analysis with the neural network program.Figure 1illus-trates a real-time digitized monochrome US image of a malignant tumor,with 58ϫ58pixels in a 1ϫ1-cm rectangle (Fig 1,A )and an image of a tumor (approxi-mately 3.1ϫ1.5cm)that was captured with a resolution of 179ϫ88pixels (Fig 1,B ).Image AnalysisA US image consists of many points with different values of gray-level inten-sity.Different tissues have markedly differ-ent textures.Benign tumors are classi-cally described as regular masses with homogeneous internal echoes,but carci-nomas are described as masses with fuzzy borders and heterogeneous internal ech-oes.Figure 2illustrates digital images of a benign tumor and a malignant tumor.We used the correlation between neigh-boring pixels on the images as classifying features of the tumor.The normalized autocorrelation coefficients (17)can be used to reflect the interpixel correlation on an image.The two-dimensional nor-malized autocorrelation coefficient ␥be-tween pixel (i ,j )and pixel (i ϩ⌬m ,j ϩ⌬n )on an image with size m ϫn can be defined as␥(⌬m ,⌬n )ϭA (⌬m ,⌬n )A (0,0),(1)whereA (⌬m ,⌬n )ϭ1(m Ϫ⌬m )(n Ϫ⌬n )(2)ϫ͚x ϭ0m Ϫ1Ϫ⌬m ͚y ϭ0n Ϫ1Ϫ⌬nf (x ,y )ϫf (x ,y )ϫf (x ϩ⌬m ,y ϩ⌬n ).Moreover,the two-dimensional auto-correlation coefficients were further modi-fied to a mean-removed version to gener-ate the similar autocorrelation features for images with different brightnessbutFigure 3.Structural graph depicts the multilayer feed-forward neu-ral network used in this study.Numbers indicate the number ofnodes.Figure 4.Diagram depicts the structure of the neural network model for tissue classification.ROI ϭregion of interest,2D ϭtwo-dimensional.Volume 213•Number 2Computer-aided Diagnosis of Solid Breast Nodules •409with similar texture.This modified ver-sion was expressed asAЈ(⌬m,⌬n)ϭ1(mϪ⌬m)(nϪ⌬n)(3)ϫ͚xϭ0mϪ1Ϫ⌬m͚yϭ0nϪ1Ϫ⌬nϫ0[f(x,y)Ϫf]ϫ[f(xϩ⌬m,yϩ⌬n)Ϫf0,whereƒwas the mean value ofƒ(x,y). The absolute value was used in Equation (3)because a negative value may be pro-duced when the mean is subtracted from the gray level of a pixel.We determined these two-dimensional autocorrelation coefficients for each US image of a breast tumor and used these coefficients as the interpixel features to distinguish between benign and malignant tumors.Neural Network ClassificationA multilayer feed-forward neural net-work contains one or more hidden layers. The function of neurons in the hidden layer is to arbitrate between the input and the output of the neural network.The input feature vector is fed into the source nodes in the input layer of the neural network.The neurons of the input layer constitute the input signals applied to the neurons in the hidden layer.The output signals of the hidden layer can be used as inputs to the next hidden or output layer. Finally,the output layer produces the output result and terminates the neural computing process.Among the algorithms used to design the multilayer feed-forward neural net-works,the back-propagation algorithm is the most popular.In general,there are two different phases in the back-propaga-tion algorithm:the forward phase and the backward phase.In the forward phase, the input signals are computed and passed through the neural network,layer by layer.Then,the neurons in the output layer produce the output signals of the neural network.During this phase,com-paring the output response of the neural network with the desired response can generate error signals.During the backward phase of the back-propagation algorithm,some free param-eters can be adjusted by referring to the error signals.This work can be used to minimize the distortion of the neural network.The multilayer feed-forward neural network has a high capability for learning and for computationalefficiency.Figure5.Illustration of the program for the neural network diagnostic model.The weights of the neural network are loaded,and then the region-of-interest subimage file is downloaded.If the output of neural network is larger than a predefined threshold of20,the result will be‘‘probably malignant.’’If the output is less than the threshold,the result will be‘‘probably benign.’’Note that the output of the neural network is multiplied by100.NNϭneural network,ROIϭregion ofinterest.Figure6.Plot depicts the mean differences between the autocorrelation coefficients for the malignant and benign tumors.The mean differences are increasing for larger⌬m and⌬n.Figure7.Plot depictsthe ROC curve for theneural network in theclassification of malig-nant and benign tumors.The A Z value of the ROCcurve is0.9560Ϯ0.0183.FPFϭfalse-posi-tive fraction,TPFϭtrue-positive fraction.410•Radiology•November1999Chen et alWe iteratively executed the back-propaga-tion learning algorithm for the training set and then produced the synaptic weight vectors that were applied to the neural network.We classified the benign and malignant tumors in the diagnostic model by applying the final synaptic weight vectors to the multilayer feed-forward neural network.We used the modified version of the two-dimensional normalized autocorrela-tion matrix for the input of the neural network.The dimension of the matrix can be fixed for an image of any size.Inthis study,both⌬m and⌬n were5,soprocessing a US image produced a5ϫ5autocorrelation matrix(ie,25autocorrela-tion coefficients).The value of␥(0,0)wasalways1for a normalized autocorrelationmatrix.Thus,except for the element␥(0,0),other autocorrelation coefficientswere formed as a24-dimensional imagefeature vector.We used a multilayer feed-forward neu-ral network with25input nodes,10hidden nodes,and one output node,asillustrated in Figure 3.The24-dimen-sional image feature vector and a pre-defined threshold of the input layer wereused as the input signals for the neuralnetwork.Moreover,the value producedby the output node was used to decidewhether a tumor was benign or malig-nant.The output value of the neuralnetwork was either0or 1.When theoutput value of a US breast image wasnear enough to1,the system classifiedthe tumor on the image as malignant.Conversely,when the output value wasclose to0,the system classified the tumoras benign.Figure4illustrates the struc-ture of the neural network model fortissue classification.Figure5illustratesthe program of the neural network diag-nostic model.In this program,the outputof the neural network was multiplied by100.Training and TestingThe receiver operating characteristic(ROC)curve and the k-fold cross-valida-tion method(18)were used to estimatethe performance of the neural network.In this study,the software packageLABROC1developed by Professor C.E.Metz,University of Chicago,Ill,was used to fitthe ROC curve.With the k-fold cross-validation method,the140images in thedatabase were randomly divided into kgroups.The first group was set aside,andthe remaining(kϪ1)groups were used totrain the neural network.The trainingprocedure was stopped when the improve-ment of error distortion was smaller than1ϫ10Ϫ6.Moreover,the maximal numberof iterations was limited to10,000.Oncetrained,the network was then tested withthe group that was set aside.The secondgroup was then removed,the remaining(kϪ1)groups were trained,and thenetwork was tested with the excludedgroup.This process was repeated until allk groups were used,in turn,as the groupthat was set aside and used for testing.Inthe simulations,k was10,and each grouphad14images.RESULTSTable1lists the mean and SD of theautocorrelation coefficients for malig-nant and benign tumors and the meandifference between the two groups.Thesubstantial mean differences of the twogroups were used to prove whether auto-correlation coefficients were good fea-tures for distinguishing malignant andbenign tumors.Moreover,with larger⌬mand⌬n,the mean difference was larger,asillustrated in Figure6.Table2lists thenumber of training iterations and errordistortions for each training set.The errordistortion was defined as the absolutedifference between the desired outputand the actual output of the neural net-work.Figure7illustrates the ROC curvefor the neural network in the classifica-tion of malignant and benign tumors.The overall performance of the neuralnetwork was evaluated by examining theROC area index A Z over the testing out-put values.Our method had a high A Zvalue of0.9560Ϯ0.0183(SD).Table3lists the performance for different thresh-old values.With a threshold of0.2,thenetwork correctly identified51of52ma-lignant tumors and82of88benign tu-TABLE2Number of Malignant and Benign Tumors,Iterations,and Error Distortions for Each Training SetTraining SetNo.ofMalignantTumorsNo.ofBenignTumorsNo.ofIterationsErrorDistortions1477910,0000.2285 2477910,000 1.1098 3477910,0000.1210 4477910,000 2.1424 547794,721 3.0023 6477910,0000.1747 7477910,000 1.2138 8477910,000 1.1468 9468010,000 1.1850 10468010,000 1.1071 TABLE3Performance of the Neural Network for Different Threshold ValuesThresholdNo.ofTumorsIncluded SensitivityNo.of BenignTumorsIncluded SpecificityNo.ofFalse-NegativeFindingsNo.ofFalse-PositiveFindings1.0500.8840.95640.9530.9250.94450.8560.9660.93260.2570.9860.93160.1580.9870.92170.0140 1.00880.00088TABLE4Number of Misdiagnosed Tumors byUsing the Neural Network at aThreshold of0.2Test Set MalignantTumorsBenignTumors10of50of921of50of930of51of940of50of950of51of960of53of970of50of980of50of990of60of8100of61of8Volume213•Number2Computer-aided Diagnosis of Solid Breast Nodules•411mors.Table4lists the number of tumors that were misdiagnosed in each test set by using the neural network at a threshold of 0.2.The accuracy of the neural network for detecting malignant tumors was95.0% (133of140),the sensitivity was98%(51 of52),the specificity was93%(82of88), the positive predictive value was89%(51 of57),and the negative predictive value was99%(82of83),as illustrated in Table 5.Table6lists the number of tumors of various specific types in this study.From the limited data in this study,the tumor type seemed to have no relationship with the ability of the network to differentiate benign and malignant tumors. DISCUSSIONWe proposed an efficient neural network diagnostic system in which interpixel cor-relations on the US image were used to differentiate benign and malignant tu-mors.The proposed system was used to diagnose breast tumors.The co-occur-rence features and the linear classifier (A Zϭ0.91)proposed by Garra et al(13) was replaced with the autocorrelation features and the neural network(A Zϭ0.96)to obtain a better result.This system adopted the multilayer feed-forward neu-ral network to classify US tumor images to distinguish benign and malignant tu-mors more accurately.The back-propaga-tion learning algorithm was used to con-struct the synaptic weights for the neural network classifier in our diagnostic sys-tem.The architecture of the neural network scheme was simple,redressed easily,and was appropriate for hardware design.Our scheme used only one type of neural network model,that is,the multilayer feed-forward neural network.Moreover, when the performance is suboptimal for new US images,these images can be added to the original training set to pro-duce a new set of synaptic weight vectorsby adjusting the free parameters.A newsynaptic weight vector for the neuralnetwork can control the performance ofthe system.Notably,the neural networkmodules can redress synaptic weight vec-tors without modifying the other func-tions.According to the experimental results,the performance of our diagnostic modelin making differential diagnoses was verygood.These results indicate that benignand malignant tumors can be distin-guished by using interpixel correlationson digital US images.From the highlysatisfactory specificity and sensitivity ofthe results,our system is expected to be auseful computer-aided diagnostic tool inthe classification of benign and malig-nant tumors on sonograms.It can pro-vide a second reading to help reducemisdiagnoses.Further studies of largertest sets of tumor images are underway.References1.Pisani P,Parkin DM,Ferlay J.Estimates ofthe worldwide mortality 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Network at a Threshold of0.2Threshold Benign Findings Malignant Findings Neural network outputϽ0.282true-negative1false-negative Neural network outputՆ0.26false-positive51true-positive Total8852 Note.—Accuracyϭ(true-positive findingsϩtrue-negative findings)/(true-positiveϩtrue-negativeϩfalse-positive findingsϩfalse-negative findings)ϭ133/140ϭ95.0%.Sensitivityϭtrue-positive findings/(true-positive findingsϩfalse-negative findings)ϭ51/52ϭ98%.Specificityϭtrue-negative findings/(true-negative findingsϩfalse-positive findings)ϭ82/88ϭ93%.Positive predictive valueϭtrue-positive findings/(true-positive findingsϩfalse-positive findings)ϭ51/57ϭ89%.Negative predictive valueϭtrue-negative findings/(true-negative findingsϩfalse-negative findings)ϭ82/83ϭ99%.TABLE6Types of TumorsType No. BenignFibroadenoma78 Fibrocystic nodule10Total88 MalignantInvasive ductal carcinoma46 Intraductal carcinoma3 Invasive lobular carcinoma3Total52412•Radiology•November1999Chen et al。