Real-world data in rheumatoid arthritis: patient similarity networks as a tool for clinical evaluation of disease activity

Abstract

Hospital databases provide complex data on individual patients, which can be analysed to discover patterns and relationships. This can provide insight into medicine that cannot be gained through focused studies using traditional statistical methods. A multivariate analysis of real-world medical data faces multiple difficulties, though. In this work, we present a methodology for medical data analysis. This methodology includes data preprocessing, feature analysis, patient similarity network construction and community detection. In the theoretical sections, we summarise publications and concepts related to the problem of medical data, our methodology, and rheumatoid arthritis (RA), including the concepts of disease activity and activity measures. The methodology is demonstrated on a dataset of RA patients in the experimental section. We describe the analysis process, hindrances encountered, and final results. Lastly, the potential of this methodology for future medicine is discussed.

Introduction

Modern medicine utilises many analysis methods that generate large quantities of data. Most of the time, this data is used in narrow, focused views of a single medical doctor in a context of a single disease. However, the data is stored electronically in hospital databases and can thus be conglomerated into complex views of individual patients. These massive datasets of seemingly incoherent data can provide new insight into medicine, not attainable by the traditional focused approach. To connect the knowledge of isolated biological processes, medical research began to view them as complex networks (Alm and Arkin 2003). Despite advancements in medical data storage, data collection has severe shortcomings. Work overload, typographical and copy-paste errors, and mistaken autocorrections are some of the culprits of the poor state of many datasets (Turchin et al. 2011; Lewis 2021). Since these problems prevail (Abeysooriya et al. 2021), data analysis methodology must adapt to overcome them.

This work presents a methodology for analysing medical data based on similarity networks. The workflow consists of data preprocessing and feature analysis, preparing partial datasets of selected features and an iterative feature reduction until a quality network with information relevant to the domain is found. The similarity network is then constructed and analysed. In “Experiment” section, the method is demonstrated using the LRNet algorithm based on local representativeness analysis (Ochodkova et al. 2017) on a dataset of rheumatoid arthritis (RA) patients.

Disease activity in rheumatoid arthritis

RA is a heterogeneous autoimmune inflammatory disease characterised by joint swelling and tenderness. The cornerstone of RA patients’ management and treatment is disease activity. Contemporary RA treatment follows a treat-to-target paradigm (Smolen et al. 2016), where the patient is treated proactively and dynamically while disease activity changes are closely monitored. This allows for an effective treatment with a minimal biological burden. Disease activity is quantified using activity measures, with the most prominent ones being DAS28 (van Gestel et al. 1998), SDAI (Smolen et al. 2003), and CDAI (Aletaha et al. 2005). DAS28 (Disease Activity Score - 28 joints counts) is considered the golden standard (van der Heijde and Jacobs 1998; Boers et al. 1994) by both the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR). DAS28 lies in a sweet spot between precision and clinical feasibility (Landewé et al. 2006). Thus, it was used as the ground truth in establishing the other activity measures, in comparing them (Leeb et al. 2005) and in this article.

The activity measures are calculated using biological markers and symptom quantifications but vary in the specific parameters used as well as the calculation formulae. The components usually include peripheral blood inflammatory markers (C-reactive protein, CRP; erythrocyte sedimentation rate, ESR), affected joint counts (swollen joints count, SJC; tender joints count, TJC) and questionnaires inspecting the patient’s general health (GH). A typical pattern in the activity measure formulas is that multiple factors add to the activity score, as seen in the DAS28-CRP formula:

$$\begin{aligned} DAS28_{CRP}=0.56\cdot \sqrt{TJC}\;+\;0.28\cdot \sqrt{SJC}\;+\;0.014\cdot GH\;+\;0.36\cdot \ln {(CRP\!+\!1)}\;+\;0.96 \end{aligned}$$

(1)

The resulting activity score is then assigned to one of four activity groups (I–IV, low to high activity). These represent the groups of patients with distinct treatment strategies. Group I contains patients in remission or with low disease activity. Patients in group II are under surveillance. Patients in group III begin active treatment, and patients in group IV are treated intensively. Since patients in individual groups require different amounts of attention from the clinician, this categorization can be simplified to non-active patients (groups I+II) and active patients (groups III+IV).

The additive nature of the activity measures causes heterogeneity in the activity groups, where patients with different parameter values can be assigned the same activity score value. Additional sources of inaccuracy are the general health questionnaires because of their subjective nature. Both the general health questionnaire filled by the patient and another one filled by the rheumatologist are subject to bias (Zhang et al. 2021; Pincus and Morley 2001).

This article is organised as follows: in “Related work and methods” section, we discuss related work; in “Methodology” section, we propose a methodology for medical data analysis and visualisation; in “Experiment” section, we demonstrate the methodology on a RA patients dataset; “Conclusions” section concludes the article.

Related work and methods

Network science in RA

Clustering analysis is less prevalent in RA studies compared to traditional statistical methods. Still, multiple studies utilizing clustering and network analysis methods were published recently. One study (Lee et al. 2014) used hierarchical agglomerative clustering to study pain in RA patients. A more recent study (Jung et al. 2021) used a combination of k-means clustering and tSNE algorithm (Van der Maaten and Hinton 2008) to study the risk of biological treatment initiation in RA patients. Another study (Platzer et al. 2022) used k-means clustering for longitudinal data to study radiological damage trajectory curves. Yet another study (Crowson et al. 2022) analyzed RA comorbidity factors to compare the clustering performance of hierarchical and k-means clustering with network analysis (with Cramer’s V distance as a dissimilarity measure).

Network analysis has been used in several studies concerning RA, mostly analysing gene co-expression (Zheng and Rao 2015; Ma et al. 2017; Xiao et al. 2021; Yadalam et al. 2022). Network analysis was also used to study RA drug-target interactions (Zhang et al. 2015; Song et al. 2019) and in RA metastudies studying common comparators of disease activity or treatment (Zhu et al. 2023; Budtarad et al. 2023). All these studies used data readily in a network form. As per our knowledge, our study is the first to use a network analysis approach to vector data in RA.

Network construction

Network science meets various applications, from social media and marketing to gene co-expression and protein modelling. In some of these applications, the data form a network, e.g. social networks (Chakraborty et al. 2018) or biological networks (Pavlopoulos et al. 2011) In these cases, network-based analysis methods can be directly applied. However, in other applications, such as coexpression modelling (Xu et al. 2002) or spectral clustering (Jia et al. 2014), the data needs to be transformed from vector data to network data before applying network analysis methods. Network construction is often necessary when solving problems arising from machine learning applications since vector data captures less information than network data. The most important information captured by networks is structural information about data relationships.

Constructing a network from vector data is a two-part process. First, the similarity (or dissimilarity) between all pairs of records is calculated using a method designed to produce a similarity (or dissimilarity) matrix. Some of the measures used are described below in the following subsection. The second part of the network construction process is sparsification, which aims to select the edges important to the constructed network.

Patient similarity networks

A patient similarity network (PSN)(Wang et al. 2014) is a network structure that comprises vertices (nodes) representing patients and weighted undirected edges representing the patients’ similarity. PSNs have been previously used to analyse patient data and to support the visualization of trends (Turcsanyi et al. 2019; Manukyan et al. 2020; Gallo et al. 2020; Mikulkova et al. 2021). One advantage of PSNs is the ease of use in multivariate analysis. The agility of the method comes from the ability to easily change the feature set used to construct the PSN and to visualize the distribution of features within the network without influencing the structure of the PSN. Additionally, PSNs have great utility in visualization, providing easily readable and understandable information to domain experts without requiring deep knowledge of network science. An example of a patient similarity network is depicted in Fig. 1.

(Dis)similarity measures

In standard notation, a network G(V, E, W) comprises a set of V vertices (nodes) representing data records, a set of (directed or undirected) edges E connecting the vertices, and a set of edge weights W. This weight usually represents common events (e.g. publications, event participation, gene co-expression), or a calculated distance or similarity between the vertices. There are many distance and similarity measures, and they all come with their advantages and caveats.

Euclidean distance is suitable for numerical data, in which the actual distance of records carries practical information. However, euclidean distance is unsuitable for high-dimensional data, where Manhattan distance is more appropriate (Aggarwal et al. 2001). Mahalanobis distance (Mahalanobis 1936) is used when the axes of n-dimensional space are not independent (redundancy in data features). Cosine similarity is used for text data and when the similarity of record proportions is of interest. There are other similarity measures used in specific applications, e.g. Jensen-Shannon distance (Endres and Schindelin 2003) for distributions, Hamming distance (Hamming 1980) for binary messages, Jaccard index (Jaccard 1901) for sets, and neighbourhood similarity measure for videos (Wang et al. 2009). Gaussian kernel (Belkin et al. 2006) is a non-linear function of Euclidean distance. This attribute is practical in network analysis and spectral clustering since Gaussian similarity can directly translate to edge weight (Nataliani and Yang 2019; Ng et al. 2001).

The selection of an ideal distance or similarity measure is thus a problem-specific issue. Moreover, network construction is further complicated by specific attributes the vector data associated with the nodes may have: data lie in a high-dimensionality space; data are derived from different distributions; data is contaminated by noise; data are probabilistic (Qiao et al. 2018).

Sparsification

However, creating links between pairs of vertices with weights according to the received (dis)similarity matrix by simply preserving edges with all calculated (dis)similarities leads to (almost) complete networks, which is not desirable. We need a high-quality network that ideally contains a giant component and is as sparse as possible to capture the relationships between vertices. Thus, sparsification is important because it improves accuracy and robustness to noise (Silva et al. 2018). We consider noise as links with small values (or large values in the case of dissimilarity) that can distort the resulting network topology. Thus, noise removal is the second important step in constructing networks from vector data.

Traditional sparsification methods include the following (Belkin and Niyogi 2003):

• Generally, a k-nearest neighbour (k-NN) network is directed. An edge from $v_i$ to $v_j$ exists if and only if $v_j$ is among the k most similar elements to $v_i$ (or among the k least distant elements in the case of dissimilarity, i.e. distance). This approach requires ordering the rows of the matrix. After sorting, for row i, links are established between vertex i and the first k items in the sorted list corresponding to the elements in the i-th row of the matrix.

• $\epsilon$-radius threshold method - an undirected edge between two nodes is added if the distance between them is smaller than $\epsilon$, where $\epsilon > 0$ is a predefined constant.

• A combination of k-nearest neighbors and $\epsilon$-radius (Silva and Zhao 2012) - both methods are combined based on the density of particular network areas. In sparse areas, we use k-nearest neighbours; in dense areas, we use the $\epsilon$-radius technique.

Our work uses the Gaussian kernel similarity measure and the LRNet algorithm to transform the vector data into a network. As Zehnalova et al. showed in previous works (Zehnalova et al. 2014a, b), data reduction based on nearest neighbour and x-representativeness of nodes provides better results than sampling in preserving structures within a dataset. Authors of Ochodkova et al. (2017) proposed algorithm LRNet based on local representativeness, displaying a similar data structure preservation capability as was seen in the work by Zehnalova et al. The algorithm evaluates the nearest neighbours and the importance of individual nodes within the network structure while not requiring the manual setting of parameters.

Community detection

Community detection algorithms are used to reveal structures within a similarity network. The terms “cluster” and “community” are similar in their meaning, both denoting a group of closely located or connected records (i.e. patients in the context of medical data). Both terms are used interchangeably in this work, depending on the context. The community detection problem is similar to the more general clustering problem. In clustering, multiple attributes (features) are considered, while in community detection, the nodes’ features are already transformed into (weighted) edges. Traditional clustering methods such as hierarchical clustering (Scott 2000) are not well suited for network data. They tend to successfully find parts of communities that correspond to highly similar records but leave some records unassigned (Newman 2004). Methods devised for network community detection are based on different approaches: modularity-based methods (Newman and Girvan 2004; Blondel et al. 2008), Bayesian methods (Yan 2016), statistical-test-based methods (Wang and Bickel 2017), and spectral clustering methods (Saade et al. 2014), to name some. Another important aspect to consider is the difference between disjoint and overlapping communities, as the solutions to these problems differ fundamentally. More information on the problem of overlapping communities, where a node can be a member of multiple communities (typically social networks), can be found in Vieira et al. (2020). Medical data does not form overlapping communities since the patients are usually divided into disjoint groups.

Our methodology utilizes the Louvain algorithm (Blondel et al. 2008). This method is based on the optimization of modularity, that is, the relative density of the edges inside communities to the edges outside communities. It works in two-step iterations, where it first assigns nodes to communities and then tries to move singular nodes to different communities and observes how the modularity of the whole network changes. The solution with the highest positive modularity change is selected as a starting point for the next iteration. Louvain algorithm is typically used for large networks but has shown good results in small-scale medical data networks (Matta et al. 2023; Trajerova et al. 2022; Turcsanyi et al. 2019). The advantage of the Louvain algorithm is that it is fully automated and requires no settings. A disadvantage is that the order of node moving can influence the outcome, and small fluctuations in solutions can be observed. The authors report these differences do not significantly influence the resulting modularity.

Clustering evaluation

Clustering evaluation is elemental in assessing clustering or community detection results. There are two distinct approaches to cluster evaluation: external and internal measures (Theodoridis and Koutroumbas 2009).

External evaluation measures, e.g. Adjusted Rand Index (Hubert and Arabie 1985), Normalized Mutual Information (Chen et al. 2010), and Jaccard index (Jaccard 1912), compare the clustering solutions with a pre-specified structure, i.e. a ground truth (external information not included among the clustered features), which reflects the known facts about the dataset, domain knowledge or expert intuition (Halkidi et al. 2002).

Internal evaluation measures are based on data vectors within the dataset. One group of internal measures, such as Dunn index (Dunn 1974), Davies-Bouldin index (Davies and Bouldin 1979), or Silhouette score (Rousseeuw 1987) that assesses the similarity (fit) between the clusters. Internal measures choose a representative point within detected clusters and use compactness and separation measures to evaluate the solution based on the distances between these points (Pascual et al. 2010). Another approach used, e.g. by the gap statistic (Tibshirani et al. 2001), assesses the explained variation of solutions (so-called “knee-of-the-curve method”). Another group of internal measures (Ben-Hur and Guyon 2003; Bel Mufti et al. 2005) assesses the stability of the behaviour of the solution. These measures define a variability measure of clustering solutions and then perform clustering on samples taken from the dataset, searching for a solution showing the lowest variation of variability measure in the sampled datasets.

A different approach to cluster evaluation is found in graph-based evaluation measures. In these, the data is first transformed into a network, which is then assessed by graph-based measures like modularity (Newman and Girvan 2004) evaluating the quality of a division of the graph, and conductance (Kannan et al. 2004) weighing groups of nodes by their importance.

Multiple studies reported no single best evaluation measure (Dimitriadou et al. 2002; Maulik and Bandyopadhyay 2002; Arbelaitz et al. 2013). A recent work (Spalenza et al. 2021) presented an algorithm combining internal and external evaluation measures, achieving significant improvements in evaluation. A similar approach is presented in our work.

Methodology

In this section, we propose a methodology for real-world medical data analysis. The workflow is depicted in Fig. 2.

Data preprocessing

As stated before, real-world medical data have many problems that need to be addressed before the analysis: typos detection, unification of varying values representing one actual state, removal of duplicated features, and remediation of incorrect Excel autocorrections. This step requires considerable insight into the domain, and thus it is advisable to involve a domain expert. Then the features are analysed using descriptive statistical methods and preprocessed according to detected distributions and their abnormalities. Features with lognormal distribution are transformed with a logarithm. These transformations, in particular, should be discussed with the domain expert since many features might have characteristics originating in the data collection method. A correct transformation is necessary to preserve these characteristics, e.g. DNA amplification primary data need to be transformed specifically with $log_2$. Then, features are normalized by rescaling to the interval [0, 1]. Finally, the presence of potential outliers is resolved.

(Dis)similarity measure selection

The measure selection is based both on the data structure, discussed in “Related work and methods” section, and on what the individual features represent and their domain relevance.

Preliminary network analysis

With a preprocessed dataset and a similarity measure selected, a preliminary network is constructed with data vectors composed of all features. This network is typically very dense, and the data structures are not discernible. However, the importance and influence of individual features can be judged based on this network. The Pearson correlation coefficient between individual feature pairs is used to assess the redundancy of features. A domain expert is vital for this step, as the significant value of a correlation coefficient is domain-specific.

Preparing feature sets

After removing features of high redundancy or low significance, features are grouped into feature sets. These are subsets of data comprising at most ten features, selected based on domain-knowledge-based preference and feature significance. The feature sets are then inspected individually.

Feature sets analysis by patient similarity networks

Individual feature sets are analysed using patient similarity networks. Iterations of the following steps are performed on each feature set:

• 1. Network construction

• 2. Network quality assessment

• 3. Network visualization and feature analysis

• 4. Feature removal

Network construction

A network is constructed using the LRNet algorithm (Ochodkova et al. 2017). However, a different network construction algorithm may be used instead without impacting the rest of the methodology. The quality of the network is assessed based on four criteria: the number of detected communities, the modularity of the network, the embeddedness of the communities, and the silhouette of the communities. Additionally, the distance of community centroids is considered. The centroids effectively represent an average patient of said community. A quality network would ideally yield distant centroids and thus cluster patients into groups with distinct feature profiles.

Network quality assessment

A network with a high number of small clusters is discarded, as too few clusters indicate insufficient intra-feature diversity. However, this happens scarcely, thanks to the feature pre-selection step. Network modularity represents the mutual separation of clusters. Embeddedness (Hric et al. 2014) represents the interconnectedness of nodes within clusters. The silhouette score of a node represents the ambiguity of its assignment to its cluster, with a low silhouette score indicating that the node is similar to not one but multiple clusters. Thus, the ideal network is highly modular, with an optimal number of highly embedded clusters with distant centroids and nodes with high silhouette scores.

A high-quality network can be of little value should the information provided be irrelevant to the aim of the analysis (clinical significance). This can be assessed by the domain expert or by inspecting the detected clusters and a class feature, provided one is present in the dataset. This class feature must not be part of the network construction feature set. The assessment is always binary, comparing one class within a cluster against the rest of the data. That is, objects of the class within the cluster are true positives, and any other objects therein are false positives. Analogously, class objects outside the cluster are false negatives, and any other objects therein are true negatives.

A dominant class is determined by assessing all classes and comparing their precision and recall values for individual cluster-class pairs. $F_1$ score, which balances the importance of precision and recall by a harmonic mean, can provide more complex information. Since the classes and clusters are usually imbalanced, multi-class Mathew’s correlation coefficient can be used to provide more understanding.

A good cluster then contains a single decisively dominant class (high precision) and a decisive majority of this class’s objects (high recall).

It should be noted, though, that this methodology aims not to find the optimal solution but rather to find a good enough solution that would be easily understandable and highly informative to the clinician. Thus, there can be multiple acceptable outcomes of this analysis.

Network visualization and feature analysis

Not every feature set has the potential to reveal data structures meaningful in the context of the domain. After obtaining a quality network, a discussion with a domain expert is necessary to assess its clinical value. For this discussion, an easily understandable visualization is necessary. This can be produced using any preferred network visualization software. The experiment in “Experiment” section utilizes Gephi software (Bastian et al. 2009) with layout algorithm ForceAtlas 2 (Jacomy et al. 2014).

Removing features

Inspecting the distribution of individual features in relation to the detected communities together with the domain expert leads to adding, removing and/or replacing individual features from promising feature sets. This may lead to changes in the network properties, especially in smaller feature sets.

Final visualization

When a satisfactory network is found, a more profound visualization step follows. First, the network layout is revised so that nodes do not overlap, and any structures too dense to discern are adjusted. This can be done automatically by modifying the parameters of the used network layout algorithm (e.g. gravity, repulsion, network sparsification, overlap prevention) or by manually adjusting the position of the nodes. Since the similarity information is carried by the edges and not by the nodes’ location, minor layout adjustments that improve the overall readability of the network are not detrimental.

Second, a visualization of “structural features” (the values which form the data vectors used in network construction) is prepared by portraying the distribution of individual features within the network. This allows for an easy understanding of how groups of patients (detected clusters) fundamentally differ. Third, a visualization of additional features is prepared. These features do not participate in the network construction, but showing their distribution within the network reveals the relationship between them and the patient groups.

Using these visualizations, the domain expert then assesses the results and determines their clinical significance.

Experiment

The Department of Internal Medicine III - Nephrology, Rheumatology and Endocrinology, University Hospital Olomouc and the Department of Immunology, Palacky University Olomouc, provided the dataset of RA patients for the experimental part. All patients within the dataset provided informed consent to use their data. Ethical committees of both the University Hospital and Palacky University approved the study. The RA dataset comprised 78 patients and 205 features, spread among three data files (clinical, protein, and blood count data) with inconsistent formats. This and other issues were solved during the data preprocessing.

The experiment aimed to find a set of RA patient features that would reach similar results of patient classification by disease activity as DAS28. There were three requirements for the task:

• 1. to use exclusively objective data (i.e. not to use general health questionnaires)

• 2. to use patient features routinely collected during the regular checkups (so that there are no or minimal changes in the clinical practice)

• 3. to include blood lipid parameters into the selected features (based on the domain knowledge of the clinicians)

Data preprocessing

First, the data files were joined, and the format was unified. The data types and unique values were inspected to remove redundant values and unify the format of individual features. These redundancies were introduced by the collaboration of multiple healthcare staff on the clinical data collection and by an overlap of clinical and blood count data. Especially problematic was the influence of Microsoft Excel’s autocorrect function on several features, where multiple numerical or textual values were changed into date values. Direct access to medical records (available due to a close collaboration with the clinicians) was invaluable in resolving these issues and data conflicts.

Based on a discussion with a clinician and the task requirements, feature pre-selection was performed. Ultimately, two patients and 52 features were removed because of missing data or irrelevance to the task. In the preprocessed dataset, the normality of data was assessed, and where necessary, the features were normalized: e.g. logarithmic transformation was applied to protein features ($log_2$) and CRP ($ln(1+x)$).

A clinician established a ground-truth feature by grouping disease activity groups into non-active patients (groups I+II) and active patients (groups III+IV).

(Dis)similarity measure selection

After inspection of the final dataset and discussion with the clinician, the Gaussian kernel was selected as a similarity measure:

$$\begin{aligned} K(x,y)=exp\left( -\frac{||x-y||^2}{\sigma ^2}\right) , \end{aligned}$$

(2)

where $\sigma ^2$ is variance and $\sigma$ was set to 0.5.

Feature sets analysis

LRNet algorithm (Ochodkova et al. 2017) using Gaussian kernel similarity measure was used for patient similarity network construction. A preliminary network was constructed to assess the significance of features. Multiple feature sets were prepared based on an analysis of this network and the feature selection factors (see “Methodology” section). Each of these sets focused on different key features recommended by the clinicians. Special attention was paid to blood lipid level parameters, as requested.

First, sets focusing on the components of activity measures were analyzed. The well-known correlation between ESR and CRP (Kotulska et al. 2015) was confirmed with Pearson correlation coefficient and matching trends observed in produced networks (Fig. 3). A correlation between the SJC and TJC was found (Fig. 3), corresponding with the reported correlation of both features with the disease activity (Riazzoli et al. 2010). Because of the high redundancy in these two pairs of features, only CRP and SJC were selected for further analyses based on their higher significance in the similarity network.

Second, sets focusing on the protein data features were analyzed. This revealed a significance of blood level of proteins CXCL10, CXCL9, CCL20, CCL7, IL-8, sOPG, and CXCL1. Another group of proteins (VEGFA, sLIFR, sIL-15RA, sCD40, and CSF1) also provided a quality network. Both networks were later discarded as clinically insignificant due to a low resolution of disease activity classification. Third, sets focusing on the clinical data were analyzed, but these did not provide relevant results. Last, the feature sets containing blood lipid features with variations of other features were inspected. The results are presented in the following subsection.

Final visualisation and results

The final result was reached in a network constructed using SJC and CRP, total cholesterol, LDL-cholesterol, and triglycerides blood levels. This result confirmed the importance of blood lipid parameters, as their addition to the network features provided considerably better results in disease activity classification than any previous feature combinations. The experiment also shows that disease activity cannot be reduced to a single parameter and requires a multivariate analysis approach.

Four patient communities were detected in the network (Fig.  4). The communities were compared to the distribution of DAS28 disease activity groups (Fig. 5). The green community contained exclusively active patients (activity groups III+IV). The red community contained predominantly active patients (88%). The blue community contained roughly the same amount of active (III+IV) and non-active (I+II) patients (47% active). The orange community contained predominantly non-active patients (11% active).

The clustering quality for the established ground-truth feature (non-active vs active patients) was assessed using precision, recall, and $F_1$ score. The values for dominant classes in individual clusters as depicted in Table 1. Figures 6, 7, 8, 9 and 10 show the distribution of the features within the network.

As is shown in Fig. 11, the profiles of the community centroids were distinct, defining profiles of average patients of the respective communities.

Several patients with activity scores different from their neighbours were discovered. Consulting a clinician revealed that three of these patients suffered from a concurrent disease or were on a medication which altered their blood lipid profiles (Fig. 12). These facts were not included in the clinical data provided.

Experiment conclusions

From the clinical point of view, the experiment found a set of objective features in RA patients that can be utilized in assessing disease activity with a performance similar to that of disease activity measures. Unlike disease activity measures, these features include easily obtainable blood lipid measures and do not include general health questionnaires. The experiment shows that disease activity in its complexity cannot be reduced to a single parameter, and multivariate analysis proves to be a good approach.

Additionally, the experiment revealed two groups with distinct profiles within high-activity patients and a group of active patients with very low swollen joint counts, neither of which was described before. Furthermore, the experiment revealed multiple patients with feature profiles strikingly different from their neighbours. It was found later that the features of these patients were influenced by external factors (other concurrent diseases and treatments) not included within the dataset. This shows that patient similarity analysis can reveal information about the patients not obtainable by the standard approach of the domain.

From the data science point of view, the experiment verified the utility of the methodology and demonstrated the usefulness of visualization of patient data as patient similarity networks. This application also shows a potential for creating a software tool for clinical practice. In such a tool, a clinician would add a new patient to the network, which would be recalculated and reconstructed. In the updated network, the patient is placed near other similar patients. Since the clinician already has extensive knowledge of these neighbours, they can make better decisions regarding the new patient.

With a large enough dataset, this tool could find use in the emerging era of telemedicine. This term encompasses any medical activity involving an element of distance (Wootton 2001) and, in a broader sense, the “backroom” processes of automating the clinical process. This tool could include options for direct contact with patients that would allow for data collection from home and general practitioners without the need to visit a hospital. This increased feasibility would provide more quality, frequent, and complete data without burdening the medical staff and the patient.

Conclusions

In this work, we presented a methodology for medical data analysis based on patient similarity network analysis. We discussed the benefits of this approach and demonstrated the methodology on a dataset of RA patients. The experiment found a set of features that complied with the experiment requirements. The patient similarity network built using these features revealed four disjoint patient subsets with differing feature profiles. The experiment also demonstrated how the analysis of patient similarity could provide additional information beyond the experiment’s aim.

Furthermore, we demonstrated the utility of the presented methodology for cooperation between a data scientist and a domain expert (clinician), which we believe will be highly important in future medicine. With the trend of telemedicine, this application could lay a basis for a software tool that would help the clinical practice and allow for more feasible and thorough data collection. This, in turn, would be valuable for further progress and development.

Fig. 1

Example of a patient similarity network. The nodes depict RA patients, and the edges depict their similarity. A Communities detected with the network. B Distribution of DAS28 score within the network on a four-point colour scale (dark blue, green, yellow, red). C Distribution of DAS28 activity groups I–IV within the network, coloured green, yellow, orange, and red, respectively

Fig. 2

Schema of a methodology workflow. Feature sets analysis is iterated until satisfactory results are achieved

Fig. 3

Distributions of correlating pairs of features. Correlating pairs are visualized in the final PSN in two columns: on the left, erythrocyte sedimentation rate and C-reactive protein; on the right, swollen and tender joint counts. A three-colour scale (blue-yellow-red) was found to provide good readability

Fig. 4

Final PSN of RA patients with detected communities. The PSN was constructed using features CRP, SJC, total cholesterol, LDL-cholesterol, and triglycerides. Four detected communities are coloured green, red, blue, and orange

Fig. 5

Final PSN showing the distribution of DAS28 activity groups. Non-active patients are coloured green (group I) and yellow (group II). Active patients are coloured orange (group III) and red (group IV). The activity trend can be clearly visible rising from low values on the right side of the network towards high values on the left. The green community contains purely active patients (III+IV). The red community contains predominantly active patients (88%). The blue community is composed randomly of active (47%) and non-active (53%) patients. The orange community contains predominantly non-active patients (89%)

Fig. 6

Distribution of CRP (C-reactive protein) in the final PSN. The distribution of CRP is visualized on a light-to-dark scale, with the high values concentrated on the left side of the network, highly correlated with the disease activity (compare to Fig. 5). Note that CRP was transformed as $\ln {\left( CRP + 1\right) }$ during preprocessing

Fig. 7

Distribution of SJC (swollen joints count) in the final PSN. The distribution of SJC is visualized on a light-to-dark scale. The distribution is correlated with the disease activity (compare to Fig. 5). A surprising profile of low SJC in patients with an elevated CRP is clearly visible within the blue community (compare to Fig. 6)

Fig. 8

Distribution of total cholesterol in the final PSN. The distribution of total cholesterol is visualized on a light-to-dark scale. Note how the trend within total cholesterol follows the same direction in the network as does the trends of other lipid parameters (see Figs. 9 and 10)

Fig. 9

Distribution of LDL-cholesterol (low-density-lipoprotein cholesterol) in the final PSN. The distribution of LDL-cholesterol is visualized on a light-to-dark scale. The trend is visually very similar to that of total cholesterol (Fig. 8), but removing LDL-cholesterol from the network reduces its quality. This shows how a purely visual assessment fails to discern data in multivariate analysis

Fig. 10

Distribution of triglycerides in the final PSN. The distribution of triglycerides is visualized on a light-to-dark scale. Note how triglycerides are low in low-activity patients, proving to be important for separation of this group in the network

Fig. 11

Centroid profiles of detected communities in the final PSN. While both red (active) and blue (mixed) communities display elevated CRP, the red community shows the lowest mean value in SJC of all communities despite many of its patients being considered active by DAS28. Four detected communities are coloured green, red, blue, and orange. CRP—C-reactive protein, SJC—swollen joints count, TC—total cholesterol, LDL-C - low-density lipoprotein cholesterol, TG—triglycerides. Rescaled [0, 1]

Fig. 12

Identified patients with concurrent disease or medication. Some patients display starkly different profiles compared to their surroundings. Some of these (highlighted in blue) proved to be suffering from a concurrent disease or to be on another medication that influenced their profiles. However, this information was not disclosed within the data and was found independently, only to be later confirmed by the clinicians. This proves that our methodology can provide more understanding than would be obtainable from the traditional approach. Non-active patients are coloured green (group I) and yellow (group II). Active patients are coloured orange (group III) and red (group IV)

Table 1 Cluster quality assessment. The table presents the dominant classes for respective clusters and the precision, recall, and $F_1$ scores used to assess them. $F_1$ score balances the importance of precision and recall (by a harmonic mean)