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Austeclino Magalhes Barros Jnior

Department of Computer Science Faculty Ruy Barbosa (FRB) Salvador, Brazil

Angelo Amncio Duarte

Department of Technology State University of Feira de Santana, UEFS Feira de Santana, Brazil

Manoel Barral Netto/Bruno Bezerril Andrade

Laboratory of Immunoregulation (LIMI) Gonalo Moniz Research Center (CPqGM/FIOCRUZ) Salvador, Brazil

Abstract In the preset study, Artificial Neural Network (ANN) and Bayesian Network (BN) techniques are evaluated as supporting tools for the diagnosis of asymptomatic malaria infection. These techniques are compared with two classical laboratorial tests for diagnosis of malaria: the light microscopy and the Nested PCR. To do this, the tests were run in a group of 380 individuals from the Brazilian Amazon. The results indicate that both innovative techniques are able to identify asymptomatically infected individuals with better accuracy than the microscopy test and are potentially useful for helping the diagnosis of asymptomatic malaria. Keywords-component: Artificial Neural Network; Bayesian Network; Asymptomatic Malaria Diagnosis

The biological explanations for the occurrence of the asymptomatic malaria are still unclear. Nevertheless, epidemiological surveys have suggested that the asymptomatic form of malaria often occurs when an individual has previously suffered a great number of malaria episodes [2]. The most pernicious result of the asymptomatic malaria is that symptomless individuals do not seek for treatment in the malaria reference centers. Thus, these individuals can remain with asymptomatic parasitemia for long periods [3] and also can transmit the Plasmodium to uninfected Anopheles mosquitoes [4]. Therefore, symptomless infected individuals can be a reservoir of parasites, hampering the disease control. Traditionally, the diagnosis of malaria is carried by looking for parasites in blood samples of an individual using a optical microscopy [5]. Although this test is considered the gold standard for malaria diagnosis, it yields no conclusive results when the individual is infected with a low burden of parasites. Since asymptomatic carriers generally present with very low parasitemia [6], the microscopy test does not generate a reliable diagnosis for this form of malaria. Thus, innovative tools are urgently needed to support a feasible approach to overcome the menace of this disease. The main objective of this study is to develop a useful tool to assist the physicians in the diagnosis of the asymptomatic malaria. To do this, we evaluated the use of Artificial Neural Networks (ANN) and Bayesian Network (BN) in the context of the diagnosis of the asymptomatic malaria. We managed to build ANNs and BNs based on immunological and epidemiological data collected from individuals from a highly endemic region for malaria in the Brazilian Amazon. The results were compared to those obtained using the light



The malaria is an infectious disease caused by protozoans of the genus Plasmodium, which are transmitted through the bite of female Anopheles mosquitoes. This infection affects mainly poor people, especially those who live in rural areas where the medical attendance is nonexistent or precarious [1]. Malaria is preventable and treatable, and besides the vector control initiatives, one of the most efficient approaches against the spread of the disease is to adequately treat infected individuals. Thus, as the therapeutic success is linked to an adequate diagnosis, the World Health Organization recommends that the search for early and precise diagnoses should be a priority action. Unfortunately, the early diagnosis is very difficult to achieve in cases which the individual has asymptomatic forms of malaria [2]. The asymptomatic malaria occurs when the individual is infected by the Plasmodium but does not present symptoms.

microscopy and the molecular test nested PCR (Polymerase Chain Reaction). Our results indicate that both innovative approaches were able to discriminate asymptomatic malaria cases with better accuracy than the light microscopy. II. METHODOLOGY The techniques of ANN e BN were tested as tools for classify individuals with asymptomatic malaria infection based on their immunological data, epidemiological data and previous infections history. Both techniques were constructed and validated with data provided by researchers of the Laboratory of Immunoregulation (LIMI), from the Goncalo Moniz Research Center (CPqGM), Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Brazil. The Artificial Neural Network technique was chosen because its capacity of learning how to classify patterns without well established categories as well as because its good robustness against noise in the samples, which provides an efficient pattern recognition method [7]. The Bayesian network was used due its ability of make decision even when their learning is based on an incomplete database [3]. The database contained 580 records with three classes of patients: uninfected; symptomatic infection and asymptomatic infection (we considered cases of Plasmodium vivax and/or Plasmodium falciparum malaria). The records included results of several laboratorial tests, socioeconomic data, environmental data and the medical history of the individuals. The data were obtained from a survey conducted in riverine communities from Rondnia State, in the southwestern Brazilian Amazon, lasting about one year, and was intended to study more deeply the causes that lead to asymptomatic malaria. The records of the patients with the symptomatic form of malaria were removed from the database since the diagnosis of these patients was not of interest in this work. The reason for such elimination is because the first symptom of the malaria is fever and, in endemic areas, it is a current practice to prescribe anti-malarial drugs for patients that present fever as a symptom. After this separation, the database ended with 380 records, and contained the same ratio of healthy patients and patients with asymptomatic malaria. A. Data Pre-Processing The raw data were pre-processed in order to reduce the number of variables. The method consisted in selecting only the relevant features in the database. Seven features were selected using the criteria defined below: Amount of previous episodes of malaria It is known that one of the causes of asymptomatic malaria is the high exposure to the illness [2]. Age Older individuals residing in the endemic areas tend to get exposed to infected mosquitoes for a lager period, possibly elevating the chance of getting higher number of malaria episodes, which increases the probability to get the asymptomatic form of this infection.

Gender Currently there are no scientific data that associates gender with asymptomatic malaria. However, pilot experiments revealed that when this feature is added to our models the quality of prediction increases. IL-10 (Interleukin 10) The IL-10 is a cytokine that has regulatory function over the immune responses. It generally increases in the context of an inflammatory process in order to reduce the immunopathology. Regarding human malaria, elevated IL-10 levels are associated with reduced severity [8,9]. Thus, patients with higher levels of IL-10 could present lower degree of inflammation, reducing the intensity of the symptoms. IFN-gamma (Interferon gamma) The IFN-gamma is a cytokine with pro-inflammatory activity. Higher levels of IFN-gamma is comomly liked to increased immune mediated tissue damage and immunopathology. We than hypothetized that in individuals with malaria, elevated levels of IFN-gamma could be related to a higher change of symptomatic disease. Time living in the endemic area Indirectly used to estimate the average number of previous malaria episodes. Use of bed net The female Anopheles mosquito, which can transmit the Plasmodium parasites, usually performs the bloodmeal late in the afternoon and remains active during large periods of the night. Therefore, the use of the bed net tends to avoid the bites during the sleep period. Nested PCR The PCR is a technique based on the multiplication of the genetic sequence of the parasite and it can yield excellent results with high specificity and sensitivity. However, such examination is difficult to perform in the malaria endemic areas because the high cost and great difficulty to maintain the laboratory support. In the scope of this study, this technique was used as a gold standard to get miss and hit rates of the evaluated methods from a comparison of results. B. Building the Artificial Neural Network The Artificial Neural Network (ANN) evaluated was the Multilayer Perceptron (MLP) because it yields good results in pattern recognition problems [10,11]. The software platform used in the experiments was the MATLAB 7 using the Neural Networks Toolbox [12]. An initial network was created with one input layer, two hidden layers and one output layer. The input layer had seven neurons, one for each feature of the patient. The hidden layers had four neurons each, and the output layer only one neuron. The activation function for the neurons was chose after comparing the results of the different activation functions available in the Neural Network Toolbox. The best results were achieved using the function tansig for the neurons in the input layer and in the hidden layers, and the function purelin for the neurons in the output layer. The training algorithm chosen was the LevenbergMarquardt because of its efficiency when dealing with

networks that have no more than a few hundreds of connections to be adjusted [13]. The training of the neural network was conduct using 300 registers from the database, approximately 80% of the total. The remaining 80 registers, about 20% of the total, were used for validation. The training data and the validation data contained the same ratio of not contaminated and asymptomatic contaminated patients in order to prevent a predominant class that could bias the results. The first configuration of the network did not reach an acceptable error rate. After some investigation it was noticed that the training data contained patients with very similar features but different diagnosis. To solve such problem a new network was created using ten neurons in each hidden layers, keeping the other as previous (seven at the input layer and one at the output layer). This new configuration was capable to better differentiate the patterns of the input data, converging to a result in 900 epochs with an error rate of 10-13. C. Building the Bayesian Network The Bayesian Network (BN) evaluated was constructed using the Bayes Net Toolbox for MATLAB [14]. The network had seven nodes, one for each feature of the patient. The construction of Bayesians Models of Knowledge involves three aspects: the learning of the network's structure, the learning of the causalities relations and the learning of the associated probabilities to the nodes. For the learning of the network's structure and the causality relations the manual paradigm was used [15]. The data pre-processing helped the modeling of each node and the definition of the arcs through the analysis of causeeffect between symptoms and its probable consequences. The definitions of cause-effect declared by the physicians and the structure of the Bayesian Network evaluated is graphically represents in Fig. 1.

The variables age, use of mosquito net, gender and previous episodes malaria, had been defined as direct causes of the malaria. Time living in endemic area was considered cause of the variable previous episodes of malaria. IFN-Gamma and IL10 were considered effects of the variable malaria.

For learning the associated probabilities to the nodes the automatic paradigm was chosen. The network used a tabular conditional probability distribution (multinomial) and the junction tree inference algorithms. It was submitted to learning associated probabilities using the database provided by FIOCRUZ and the end of learning, the tables of probability of all nodes were generated [14]. The algorithms used to train the BN required the continuous variables be discretized [16]. Discrete variables are variables that assume values in a subgroup of the natural numbers [15]. In the database, the variables that had continuous values were: age, previous episodes malaria, IL10, IFN-gamma and time living in the endemic area. The discretization of these variables was ruled with the assistance of the clinicians and immunologists from the FIOCRUZ and is shown in table I.

Variable Previous episodes malaria None 1-4 5 - 10 > 10 Time housing endemic area 2 3 to 10 > 10 Age 5 - 15 16 - 30 31 - 59 60 Serum IL-10 (pg/mL) 46 > 46


None Low Regular High

Low Regular High

Low Regular High Very Low

Regular High Regular High

Figure 1. Graphical representation of structure of Bayesian Network evaluated.

Serum IFN- (pg/mL) 198 >198

III. RESULTS The experiments were conducted in order to evaluate the precision of the Artificial Neural Network and the Bayesian Network in the diagnosis of the asymptomatic malaria using as reference the results of to the microscopy test. The comparison was made using 80 records of patients, of whom 40 were of patients with asymptomatic malaria and 40 of healthy individuals. In an attempt to analyze the quality of classifiers, we used the classical Receiver Operating Characteristic [17]. The ROC curve is a simple and robust graphical method that allows study the variation of sensitivity (true-positive) and specificity (true-negative) of a classifier [17]. In a ROC graph the Y axis represents the sensitivity and the X axis represents (1specificity). An ideal classifier is represented by a point in upper left corner (0,1), indicating 100% of sensitivity and 100% of specificity. In diagnostic terms, the sensitivity is defined as the capacity that a test or exam has to detect the sick individuals, and the specificity is defined as the capacity that a test or exam has to correctly separate the healthy individuals. The sensitivity is obtained dividing the number of positive (illness presence) samples correctly detected from the total number of positive samples in the data. Similarly, the specificity is obtained dividing the number of negative (noillness presence) samples correctly detected from the total number of negative samples in the data. For all tests, we used a 0.9 cut-point, which is a value that can be arbitrarily selected among all possible values for the variable of decision [17]. When the diagnostic technique used generates a result above of the cut-point the patient is classified as positive (illness presence), and below which the patient is classified as negative (no illness). The miss and hit rates of each evaluated method was obtained comparing the diagnoses with the most reliable method to malaria diagnosis: the Nested PCR [5]. The PCR is a technique based on the multiplication of the genetic sequence of the parasite and it can yield excellent results with high specificity and sensitivity [18,19]. Unfortunately, because of its high cost and technical complexity the PCR is restricted to research purposes in reference laboratories. A. Results for the Artificial Neural Network (ANN) The ANN presented 67.5% of sensitivity and 92.5% of specificity, and has correctly diagnosed 80.0% of the 80 individuals separated for testing the method. The Fig. 2 shows the ROC curve illustrating the diagnoses generated by ANN. B. Results for the Bayesian Network (BN) The BN presented 37.5% of sensitivity and 97.5% of specificity, and has correctly diagnosed 67.0% of the 80 individuals separated for testing the method. The Fig. 3 shows the ROC curve illustrating the diagnoses generated by BN.
Figure 3. ROC curve representing the diagnoses generated by Bayesian Network. The point P on the ROC graph represents 97.5% of specificity and 37.5% of sensitivity.

Figure 2.

ROC curve representing the diagnoses generated by ANN. The point P on the ROC graph represents 92.5% of specificity and 67.5% of sensitivity.

C. Results for the Microscopy Test The microscopy yielded 22.5% of sensitivity and 100% of specificity, thus, correctly diagnosed 61.25% of the 80 individuals separated for testing. The Fig. 4 shows equivalent ROC curve.

Figure 5. Variation of the percentages of sensitivity, specificity and hits of the ANN and BN techniques relative to the microscopy test. Figure 4. ROC curve representing the diagnoses generated for the microscopy test. The point P represents 100% of specificity and 22.5% of sensitivity.

IV. COMPARING ANN, BN AND MICROSCOPY TEST The table II shows the comparison between specificity and sensitivity results for the ANN and BN computational methods and microscopy test for the same group of 80 individuals. It can be verified that the percentage of hits achieved using the ANN technique is 18.75% greater that the percentage of obtained using the microscopy test. The BN method also presented a percentage of hits greater that the microscopy test (6.25%). The percentage of specificity in the microscopy test is 100%, what can be explained because this method generates positive diagnosis only when the Plasmodium is found in the patients blood sample, therefore a false positive is improbable in this test. On the other hand, the diagnosis produced by the ANN and BN techniques presented a little lower specificity ratio, 92.5% and 97.5% respectively, because those methods work with artificial models for classifying a patient. The sensitivity obtained by the ANN and BN techniques were 45% and 15% greater than the percentage of false negative of the Microscopy test. The Fig. 5 summarizes the variation of the percentages of hits, specificity and sensitivity of the three techniques.

A special care must be taken about the evaluation of the sensitivity and specificity rates. Lower specificities rates indicate a high rate of false positive and false-positive results may induce a psychological trauma to patients. Furthermore, the patient will subject to the unnecessary treatment of taking anti-malarial medicines. On the other hand, lower sensitivities rates indicate high rates of false-negative. False-negative results make that patients do not take the anti-malarial medicines when he or she really needs these medicines. Furthermore, untreated patients function as a parasite repository and may become a contamination vector that can increase the probability of contamination of healthy individuals in the region where they live. Therefore, in the context of asymptomatic malaria, it seems to be less dangerous to have false positives than falsenegatives diagnoses, because the damage that an infected individual with asymptomatic malaria may suffer or induce if he or she does not receive the treatment is greater than the damaged that a healthy individual may suffer if he or she receives a false diagnosis of malaria and be subject to an unnecessary treatment. V. CONCLUSION

Diagnostic Method ANN BN Microscopy

Sensitivity % 67.5 37.5 22.5 A* 27 15 9

Specificity % 92.5 97.5 100 A* 37 39 40 %

Hits A* 64 54 49

The asymptomatic malaria is a risk factor for the propagation of malaria in endemic areas where there is a high number of mosquitoes. The Microscopy test is ineffective for the diagnosis of the asymptomatic malaria, because this exam has low sensitivity when the individual presents a low number of parasites, what is the typical case in individuals with the asymptomatic form. The Nested PCR laboratorial test is more effective than the Microscopy test for diagnosis of asymptomatic malaria [18, 19]. however, it becomes impracticable in large scale because the complexity of the necessary equipment and, consequently, the high cost of the exam. Therefore, the development of a practical, robust and cheap alternative for the diagnosis of the

80.0 67.0 61.25

malaria is an important goal for many health institutions around the world. This article presented an evaluation of Artificial Neural Network (ANN) and Bayesian Network (BN) techniques as tools for the diagnosis of the asymptomatic malaria. Those techniques presented higher sensitivity than the Microscopy test and are far less costly compared to the Nested PCR test. The ANN presented better classification of patients with asymptomatic malaria, and yielded the best results. The BN have not reached the same good results achieved by the ANN. Nevertheless, BN presented better results than the obtained with the microscopy tests for the evaluated patients, indicating that is necessary to improve the cause-effect structures with new variables that can be relevant to the context studied or with more precise conditional tables. Although the techniques of ANN and BN have presented lower specificity rates compared with the Microscopy test, they have presented higher sensibility rates. This indicates that the ANN and BN can be more suitable to carry through the diagnosis in endemic regions where the prevalence of asymptomatic infection is high. From the two computational techniques, the ANN presented the highest hit-rate and sensitivity rate. The next steps in this research will be the development of a multiplatform executable program, allowing the use of the system in mobile phones for example, so that a doctor can easily make the diagnosis even in remote areas. We also expect to access a new set of samples collected from a new groups of individuals, in order to refine the ANN and BN or to use a different computational technique (like fuzzy logic) to create a more robust diagnosis technique for asymptomatic malaria. Furthermore, we intend to make a data mining in the database used in order to find other relevant features that can be used to construct a better classifier. REFERENCES
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