Predicting the survival of primary biliary cholangitis patients

Citation: Ferreira, D.; Neto, C.; Lopes, J.; Duarte, J.; Abelha, A.; Machado, J. Predicting the Survival of Primary Biliary Cholangitis Patients. Appl. Sci. 2022,12, 8043. https://doi.org/10.3390/ app12168043 Academic Editor: Keun Ho Ryu Received: 1 July 2022 Accepted: 8 August 2022 Published: 11 August 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). applied sciences Article Predicting the Survival of Primary Biliary Cholangitis Patients Diana Ferreira 1, Cristiana Neto 1, José Lopes 2, Júlio Duarte 1, António Abelha 1and José Machado 1,* 1Algoritmi Research Center, University of Minho, 4710 Braga, Portugal 2Department of Informatics, University of Minho, 4710 Braga, Portugal *Correspondence: [email protected]; Tel.: +351-253604430; Fax: +351-253604471 Abstract: Primary Biliary Cholangitis, which is thought to be caused by a combination of genetic and environmental factors, is a slow-growing chronic autoimmune disease in which the human body’s immune system attacks healthy cells and tissues and gradually destroys the bile ducts in the liver. A reliable diagnosis of this clinical condition, followed by appropriate intervention measures, can slow the damage to the liver and prevent further complications, especially in the early stages. Hence, the focus of this study is to compare different classification Data Mining techniques, using clinical and demographic data, in an attempt to predict whether or not a Primary Biliary Cholangitis patient will survive. Data from 418 patients with Primary Biliary Cholangitis, following the Mayo Clinic’s research between 1974 and 1984, were used to predict patient survival or non-survival using the Cross Industry Standard Process for Data Mining methodology. Different classification techniques were applied during this process, more specifically, Decision Tree, Random Tree, Random Forest, and Naïve Bayes. The model with the best performance used the Random Forest classifier and Split Validation with a ratio of 0.8, yielding values greater than 93% in all evaluation metrics. With further testing, this model may provide benefits in terms of medical decision support. Keywords: classification; data mining; predictive models; primary biliary cholangitis 1. Introduction In terms of the disease’s definition, Primary Biliary Cholangitis (PBC) is described as being a chronic, progressive cholestatic liver disease of unknown cause [ 1 ], but because of autoantibodies, it is generally thought to be an autoimmune disease [ 2 ], that eventually leads to liver failure and the need of a liver transplantation [ 1 ]. PBC was formerly known as Primary Biliary Cirrhosis, but the designation was around 2015, because cirrhosis was not a necessary condition for the diagnosis of this disease [3]. PBC is hypothesised to be related to environmental exposure in genetically vulnerable individuals. Prominent clinical features include fatigue, pruritis, jaundice, xanthomas, osteoporosis, and dyslipidemia [ 4 ]. Additionally, it is known that about 90% of patients with PBC are women and that the disease is normally diagnosed in patients between the ages of 40 and 60 years [ 2 ], meaning that genetic factors, sex, and age are commonly associated as risk factors of PBC. Moreover, previous research has shown that the risk of PBC can be increased by alterations in sex hormones in women over time [5]. Nowadays, its diagnosis is becoming more common as a result of increased physician recognition and the widespread use of automated blood testing and the antimitochondrial antibody test, which is somewhat specific for this disease [ 1 ]. Given current screening methods, PBC is now often diagnosed when the patient is still asymptomatic, with abnormal liver biochemistry and/or Antimitochondrial Antibodies (AMA) identified in blood during a routine check-up or as part of the work-up for an associated disorder [ 6 ]. The Mayo Risk score is the most widely used and the best prognostic system [4]. In this study, a public dataset of 418 patients diagnosed with PBC at various stages during the disease’s progression, containing 19 important features to the identification and monitoring of the disease, is examined. Since the chosen dataset contained information Appl. Sci. 2022,12, 8043. https://doi.org/10.3390/app12168043 https://www.mdpi.com/journal/applsci Appl. Sci. 2022,12, 8043 2 of 15 about the patient’s status, i.e., if the patient was alive, in need of a liver transplant, or deceased, this study focused on the prediction of the survival of patients diagnosed with PBC using Data Mining (DM) techniques. DM is useful for analysing and exploring large datasets in order to discover meaningful patterns and rules [ 7 ]. The implementation of DM techniques can also facilitate the reduction in medical errors, enhance patient safety, standardise clinical practice, and improve patient outcomes [ 8 ]. Since the dataset is labelled, this study will use supervised techniques, which can include regression and classification [ 9 ]. As expected, and as previously stated, the focus of this paper will be on classification techniques, with different classifiers from the RapidMiner software being used to predict PBC patients’ status, i.e., the label attribute, which corresponds to the attribute that predicts the patients’ survival or non-survival. With this study, it will be possible to identify which patients have a greater chance of survival. As a result, hospitals and healthcare professionals will be able to concentrate their efforts, time, resources, and treatment options on patients who are more likely to survive. On the other hand, in terms of research, the cases of patients classified as patients who will not survive can be used for the search and development of innovative treatments. The paper is structured in five sections. After introducing the problem, it will be presented the Related Work Section 2, regarding works related to the PBC topic. This section is followed by a detailed description of the DM process carried out using the CRossIndustry Standard Process for Data Mining (CRISP-DM) methodology in the Materials and Methods Section 3. Next, an analysis of the obtained results and its interpretation is performed in the Discussion Section 4. Finally, the Conclusions Section 5, summarises the whole process, draws the final conclusions based on the results achieved, and presents a brief proposal for future work. 2. Related Work The subject of this paper has been mentioned and studied in several articles, given the fact that it is not only a chronic liver disease but also a rare condition that is often only treated through liver transplantation. As a result, the majority of the studies in the literature are devoted to improving treatment management and evaluating the influence of certain substances in disease spread. Reference [ 10 ] studied the progression of PBC in 312 patients treated at the Mayo Clinic between January 1974 and May 1984. This study was based on repeated patient visits (a total of 1945 patient visits) that were important to evaluate the changes in the prognostic variables of PBC, such as age, albumin value, prothrombin time, bilirubin value, and edema. This dataset is similar to the one used in this study but not exactly the same. Using these data and the Cox proportional-hazards regression model, it was built an updated model to be used in the short-term survival prediction at any stage of the disease. It was concluded that the new updated model makes more accurate predictions in terms of short-term survival than the original Mayo model, meaning that the Mayo model is still the best choice for predicting the patient’s survival for more than 3 years, but for periods up to 2 years, this new model offers a more accurate estimation of PBC patients’ survival. The biochemical response to ursodeoxycholic acid (UDCA) in PBC was analysed by [ 11 ] and is related to the long-term prognosis of the disease, thus allowing the identification of the patients’ need of new therapeutic approaches. The aim of this study was to determine, in a population of patients in an early-stage of the disease, the most efficient biochemical response to UDCA, allowing the prediction the absence of poor outcome, as described by liver-related death, liver transplantation, complications of cirrhosis, or histological evidence of cirrhosis development. A similar study was developed by [ 12 ], in which it was explored the effect of azathioprine on the survival of PBC patients. Using a randomised clinical trial containing 248 patients, where the immunosuppressive medication azathioprine was given to 127 of those patients, with the remaining 121 patients receiving placebo, which has no therapeutic Appl. Sci. 2022,12, 8043 3 of 15 value. Similarly to the approach taken by [ 10 ], it was applied a Cox multiple regression analysis and an adjustment relative to the imbalance between the treatment groups. The therapeutic effect of azathioprine has been shown to reduce the risk of non-survival to 59% of those observed with placebo, as well as to improve the survival time by up to 20 months for the average patient, revealing a statistical significance of azathioprine therapy. In a global manner, as it can be seen from the previous articles, there is more emphasis in the literature on the analysis of treatments for PBC and not specifically on its prognosis or evolution. Thus, more studies are needed to broaden the knowledge and understanding on the diagnosis of this condition as early as possible [ 13 ]. Machine learning algorithms can be used to perform early diagnosis and risk stratification, as well. Hence, developing diagnostic algorithms for PBC patients based on demographic variables, symptomatology, and laboratory results is a resourceful tool for improving the quality of clinical practice. We present a novel DM approach for PBC where the emphasis is the use of classified data to predict the survival of patients diagnosed with PBC. Several experiments were carried out, in which different DM techniques and feature selection setups were taken into account. Such knowledge is particularly useful to perform early diagnosis and risk stratification, thus improving the quality of clinical practice and lowering the mortality rate of patients diagnosed with PBC. 3. Materials and Methods The DM process followed the CRISP-DM methodology, which is one of the most used for increasing the success of a DM project [ 14 ]. One of the main advantages of its utilisation is that it allows the construction and implementation of a DM model that can be used in a real environment, helping to support business decisions [ 15 ]. CRISP-DM is defined as a cyclic process, in which six phases are defined [16,17]: • Business Understanding, where it is defined the project objectives and requirements, as well as the Data Mining problem definition; • Data Understanding, in which the initial data are collected, proceeded by their familiarisation and analysis, where initial conclusions are taken in terms of data quality problems and obvious results; • Data Preparation, characterised by the selection of data (decision of the important attributes to analyse), data cleansing (remove duplicates, decision of the best approach in terms of missing values and outliers), data transformation (includes production of derived attributes or even entire new records), and, in case of unbalanced datasets, data sampling, by applying oversampling or undersampling techniques to reduce the imbalance in the classes’ distribution; • Modeling, where the modeling techniques that will be used are selected followed by their execution on the given dataset to compare its results; • Evaluation, determines if the results meet business objectives and identifies business problems that should have been addressed earlier; • Deployment, the final phase of the methodology, which will not be taken into consideration in this article, refers to the practical implementation of the resulting models, where we take the evaluation results and determine a strategy for their development [18]. Figure 1illustrates the lifecycle of the CRISP-DM methodology. The RapidMiner software was the tool selected to conduct this study, which is a prominent data science platform that binds data preparation, Machine Learning, and predictive model deployment. Its user-friendly interface, efficiency, and wide range of algorithms and techniques available were additional factors for this choice. All methods were performed in accordance with the relevant guidelines and regulations. In the following subsections, each phase of the CRISP-DM will be discussed in relation to the data of PBC patients. Appl. Sci. 2022,12, 8043 4 of 15 Figure 1. Stages of the CRISP-DM lifecycle. 3.1. Business Understanding The current DM process focuses its business objective on the study of the health status of patients with PBC. With this business objective in mind, the study could pursue two different approaches, predict the survival/non-survival of patients with PBC, or determine the need of surviving patients for liver transplantation. However, in this article, and in the processing of the given data, it was only taken into consideration a binary classification, namely, the survival/non-survival of patients with PBC. Additionally, there are some aspects that can influence the business goal. This is the case, for example, of the type of drug administered to patients, where two different types of drugs—D-penicillamine or placebo—can be administered. Based on the number of deceased patients vs. the number of non-deceased patients, the effect of these drugs may be helpful, because if a drug type has a lower number of deceased patients associated in comparison to the other drug, it can be assumed that this type of drug may have more success in the survival of patients with PBC, which is very helpful to physicians who are medicating patients with this condition. It is also essential to check the influence of the patient’s histologic stage. To do this, it is important to understand the different stages of the condition: • Stage 1—known as portal hepatitis; • Stage 2—associated with periportal hepatitis; • Stage 3—septal fibrosis, bridging necrosis, or both; • Stage 4—final stage, commonly referred to as cirrhosis. Obviously, the death rate can be expected to be higher in patients with stage 4 PBC, which means that it is probably more difficult to save them than to save a patient with stage 1 or stage 2 PBC. The study schema for this project is shown in Figure 2. This schema shows the structuring main steps of the research presented in this paper. Each one of these steps will be detailed in the next sections. After defining the business goal, the need to analyse the data arose. Hence, the next subsection focuses on the data understanding stage of the CRISP-DM methodology. Appl. Sci. 2022,12, 8043 5 of 15 Figure 2. Project plan of steps taken in the present study. 3.2. Data Understanding The data used in the present study are from a Mayo Clinic trial in PBC of the liver conducted between 1974 and 1984 [ 19 ]. The dataset contains information about 418 patients with PBC. The information of each patient, defined in the dataset as a data instance, consists of a set of 19 variables plus the patient’s id, which was later disregarded from the study. The description of the attributes is presented in Table 1. Table 1. Description of the attributes in the given data before the modifications made in the Data Preparation phase. Variable Type Missing Values Range Average Description futime Integer 0 [41–4795] 1917.78 number of days between registration and the earlier of death or study analysis time age Integer 0 [9598–28,650] 18,533.35 age of each patient, in days sex Integer 0 [0–1] 0.90 0 = male; 1 = female status Integer 0 [0–2] 0.83 0 = alive; 1 = needs a liver transplant; 2 = deceased drug Integer 106 [1–2] 1.49 1 = D-penicillamine; 2 = placebo stage Integer 6 [1–4] 3.02 1 = portal hepatitis; 2 = periportal hepatitis; 3 = septal fibrosis, bridging necrosis, or both; 4 = cirrhosis ascites Integer 106 [0–1] 0.08 existence of abnormal accumulation of fluid in the abdomen: 0 = no; 1 = yes hepato Integer 106 [0–1] 0.51 existence of hepatomegaly (enlarged liver condition): 0 = no; 1 = yes spiders Integer 106 [0–1] 0.29 existence of blood vessel malformations in the skin (spiders): 0 = no; 1 = yes edema Real 0 [0–1] 0.10 accumulation of fluids in body tissues: 0 = no edema and no diuretic therapy for edema; 0.5 = presence of edema but without diuretics or edema resolved by diuretics; 1 = presence of edema despite diuretic therapy bili Real 0 [0.30–28] 3.22 amount of serum bilirubin (mg/dL) chol Integer 134 [120–1775] 369.51 amount of serum cholesterol (mg/dL) albumin Real 0 [1.96–4.64] 3.50 amount of albumin (gm/dL) copper Integer 108 [4–588] 97.65 amount of copper in urine (µg/day) Appl. Sci. 2022,12, 8043 6 of 15 Table 1. Cont. Variable Type Missing Values Range Average Description alk_phos Real 106 [289–13862.40] 1982.66 amount of alkaline phosphatase (U/L) sgot Real 106 [26.35–457.25] 122.56 amount of Serum Glutamic Oxaloacetic Transaminase (U/mL) trig Integer 136 [33–598] 124.70 number of triglycerides (mg/dL) platelet Integer 11 [62–721] 257.03 number of platelets per cubic mL/1000 protime Real 2 [9–18] 10.73 prothrombin time (in seconds), to evaluate the extrinsic pathway of coagulation As already mentioned, this study is based on a binary classification, namely, the survival/non-survival of patients with PBC, so the status attribute was transformed to the binary type, where patients that were in need of liver transplantation were considered surviving patients. Lastly, it was also important to underline some interesting aspects of the given data. Therefore, Figure 3presents the distribution of the label attribute—status—and the sex attribute, where it can be seen that the data are a little unbalanced in the label attribute and that there are much more women than men associated with this disease (which goes as expected in a real life scenario, as described in Section 1). Figure 3. ( a ) Visualisation of the value discrepancy in the sex attribute. ( b ) Data distribution by attribute. Appl. Sci. 2022,12, 8043 7 of 15 When comparing the label attribute and the stage attribute (Figure 4), it can also be concluded that, as expected, there are more deceased patients in the last stage of the disease—stage 4—followed by stage 3, which makes sense, given the fact that a patient is more likely to pass away when the disease is more advanced. Figure 4. Association of the status attribute (label) and the stage attribute, where the alive patients are represented by the green bars and the deceased patients by the blue bars. 3.3. Data Preparation First, as mentioned in the Business Understanding phase, the status attribute only considered the values referring to patient’s survival/non-survival. In order to do so, patients in need of a liver transplant were referred to as surviving patients, which means that patients with a status value equal to 1 were replaced by a status value equal to 0. Additionally, patients with status value equal to 2 were replaced by a status value equal to 1, meaning that this attribute can now only take the value 0 or the value 1, where 0 stands for the patient’s survival and 1 stands for the patient’s death, making it a binomial attribute. In addition, there was also the need to change the data type of some values, since most of them had the integer type, which was not the most accurate choice. Thus, the attributes status,sex,ascites,hepato,spiders, and drug were transformed to the binomial type, since they can only take two values, and the attributes edema and stage were transformed to the polynomial type, given the fact that they can take more than two specific values. After adjusting the data types, it was important, as seen in Table 1, to deal with missing values in some attributes. Since the dataset has a reduced number of instances (patients), the best way to deal with these missing values is to replace them. To do so, these missing values were estimated by learning models for each attribute, with the exception of the label attribute. As a result, the missing values were treated by imputing the values resulting from the Neural Network (NN) model for missing numerical values and from the Decision Tree (DT) model for missing nominal values. In terms of outlier removal, it was established that there were no outliers present in the dataset. More precisely, the possible outliers present in the given data were probably related to unusually high/low natural values, meaning that these values were not related to errors in the dataset itself, and consequently, there was no need to remove them. Lastly, since there were numerous attributes related to substances found in the human body in different scales, where the higher values associated with higher scales would lead to an unrealistic influence, it became crucial to normalise each of these numerical attributes to the same scale. A minmax normalisation was therefore performed, so that all numeric attributes were at the same scale, with values ranging between 0 and 1, in order to correctly Appl. Sci. 2022,12, 8043 8 of 15 determine which ones are actually more significant, leading to a more accurate use of the dataset. 3.4. Modelling In this phase, the data resulting from the data preparation phase are used to feed the different Data Mining Models (DMMs) through the usage of the RapidMiner software. Given the fact that this is a classification approach, the following predictive models were used: DT, Random Forest (RF), Random Tree (RT), and Naïve Bayes (NB), using a finetuning process through the optimisation of the parameters of each model. DT is an algorithm widely used for classification and regression tasks. The process of creating a DT works by greedily selecting the best split point in order to make predictions and repeat the process until the tree has a fixed depth. After the tree is constructed, it is pruned to improve the ability of the model to generalise to new data [20]. A common drawback of DTs is that they tend to overfit the training data. RF is one way to address this problem. RF is essentially a collection of DTs where, initially, a bootstrap sample is selected from the training data (random sample obtained with replacement) with the aim of inducing DT. This step is repeated until a set of DTs was created, each of which has its own predictive value. Hence, the final prediction is achieved by combining the output of all trees, which corresponds to the most frequent output of the ensemble [21]. RT works exactly like DT, with one exception: for each split, only a random subset of attributes is available. RT works similar to Quinlan’s C4.5 or CART, but it selects a random subset of attributes before being applied [ 22 ]. Although the first three algorithms are tree-based, they do not perform the same. Because decision trees are an effective method of decision-making, it was decided to test different tree variations. In addition, the NB classifier was also used in this study. It is based on the Bayes Theorem, which is a probabilistic theorem that is used to find out the probability of something happening ( A ) by knowing that ( B ) has occurred, as mathematically expressed in (1) . Therefore, given the problem at hand, the A variable can be considered the label/target, the attribute status. The B variable can be extended and seen as the rest of the features of the dataset [20]. P(A|B) = P(B|A)×P(A) P(B)(1) Following the selection of the models, it was necessary to define the different sampling methods for testing. Full training was not considered in this study; instead, three sampling methods were considered, namely, Cross Validation (CV), using 10 folds, and Split Validation (SV), with a split ratio of 0.7 and a split ratio of 0.8. CV uses all data for training, whereas SV uses a certain percentage for training and the remaining for testing, as can be seen in Figure 5. Two missing values approaches were tested: the application of data replacement and the removal of instances with missing values. In addition, three data approaches were taken into consideration, the original dataset, the dataset with oversampling, and the dataset with undersampling. Oversampling consisted of the replication of cases of the minority class until a balanced distribution was achieved between the two classes. On the other hand, undersampling consisted of the removal of instances from the majority class until a balanced distribution was achieved. Both oversampling and undersampling techniques were achieved using the sampling operator, which creates a sample from a dataset by selecting examples randomly. The number of examples in the sample can be specified on absolute, relative, or probability basis depending on the setting of the sample parameter. The class distribution of the sample can be controlled by the balance data parameter. Additionally, to evaluate which attributes were the most relevant in the label’s prediction, several scenarios were defined using different sets of attributes. This selection was made based on the feature weight analysis using two different operators: Appl. Sci. 2022,12, 8043 9 of 15 • The Weight by Correlation operator, which calculates the weight based on the correlation of the feature with the status attribute (label). Highly correlated attributes can erroneously influence the label’s prediction, which could be misleading or disguise the other features. Consequently, this operator was applied in the definition of the scenarios, where the attributes with high weights were eliminated, as they could be deceptive to the label’s prediction. • The Weight by Information Gain Ratio operator, which calculates the weight of each attribute related to the status attribute (label) through the usage of the information gain ratio, which means that the higher the weight of an attribute, the more relevant it is to the forecast. Consequently, this operator was applied in the definition of the scenarios, where the attributes with lower weights were eliminated, since they do not have much impact in the label’s prediction. Figure 5. Comparison between Split and Cross Validation functioning. Such results are displayed in Figure 6, where the Weight by Correlation operator is shown in Figure 6a and the Weight by Information Gain Ratio operator is displayed in Figure 6b. Thereby, the scenarios defined were: • S1: {All attributes}; • S2: {All attributes, except drug,sex, and stage}, where the attributes with weight inferior to 0.05 were eliminated, consistent with the information viewed in the Weight by Information Gain Ratio operator; • S3: {All attributes, except age,drug,edema,hepato,sex,sgot,spiders, and stage}, where, similar to the S2 scenario, a threshold above 0.1 was applied, meaning that the attributes with weight below 0.1 were eliminated, in accordance with the Weight by Information Gain Ratio operator; • S4: {All attributes, except bili}, since it is the attribute with higher weight correlation, according to the Weight by Correlation operator. Conclusively, each attempt can be described as belonging to an Approach (A)= {Classification}, being associated to a Data Mining Technique (DMT) = {Decision Tree, Random Forest, Random Tree, Naïve Bayes}; a Scenario (S) = {S1, S2, S3, S4}; a Sampling Method (SM) = {Cross Validation, Split Validation 0.7, Split Validation 0.8}; a Missing Values Approach (MVA) = {Replacement (MVA1), Deletion (MVA2)}; a Data Approach (DA) = {None (DA1), Oversampling (DA2), Undersampling (DA3)}; and a Target (T) = {status}, as expressed in (2): DMM ={A,S,DMT,SM,MVA,DA,T}(2) In total, 288 models were induced according to (3): DMM ={1(A)×4(S)×4(DMT)×3(SM)×2(MVA)×3(DA)×1(T)}(3) The next phase shows the results achieved for each of these attempts.