# Supervised Clustering Based on DPClusO: Prediction of Plant-Disease Relations Using Jamu Formulas of KNApSAcK Database

Authors: Sony Hartono Wijaya; Husnawati Husnawati; Farit Mochamad Afendi; Irmanida Batubara; Latifah K. Darusman; Md. Altaf-Ul-Amin; Tetsuo Sato; Naoaki Ono; Tadao Sugiura; Shigehiko Kanaya
Journal: BioMed Research International
 (2014)

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## Abstract

Indonesia has the largest medicinal plant species in the world and these plants are used as Jamu medicines. Jamu medicines are popular traditional medicines from Indonesia and we need to systemize the formulation of Jamu and develop basic scientific principles of Jamu to meet the requirement of Indonesian Healthcare System. We propose a new approach to predict the relation between plant and disease using network analysis and supervised clustering. At the preliminary step, we assigned 3138 Jamu formulas to 116 diseases of International Classification of Diseases (ver. 10) which belong to 18 classes of disease from National Center for Biotechnology Information. The correlation measures between Jamu pairs were determined based on their ingredient similarity. Networks are constructed and analyzed by selecting highly correlated Jamu pairs. Clusters were then generated by using the network clustering algorithm DPClusO. By using matching score of a cluster, the dominant disease and high frequency plant associated to the cluster are determined. The plant to disease relations predicted by our method were evaluated in the context of previously published results and were found to produce around 90% successful predictions.


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## Body

## 1. Introduction

Big data biology, which is a discipline of data-intensive science, has emerged because of the rapid increasing of data in omics fields such as genomics, transcriptomics, proteomics, and metabolomics as well as in several other fields such as ethnomedicinal survey. The number of medicinal plants is estimated to be 40,000 to 70,000 around the world [1] and many countries utilize these plants as blended herbal medicines, for example, China (traditional Chinese medicine), Japan (Kampo medicine), India (Ayurveda, Siddha, and Unani), and Indonesia (Jamu). Nowadays, the use of traditional medicines is rapidly increasing [2, 3]. These medicines consist of ingredients made from plants, animals, minerals, or combination of them. The traditional medicines have been used for generations for treatments of diseases or maintaining health of people and the most popular form of traditional medicine is herbal medicine. Blended herbal medicines as well as single herb medicines include a large number of constituent substances which exert effects on human physiology through a variety of biological pathways. The KNApSAcK Family database systems can be used to comprehensively understand the medicinal usage of plants based upon traditional and modern knowledge [4, 5]. This database has information about the selected herbal ingredients, that is, the formulas of Kampo and Jamu, omics information of plants and humans, and physiological activities in humans. Jamu is generally composed based on the experience of the users for decades or even hundreds of years. However, versatile scientific analyses are needed to support their efficacy and their safety. Attaining this objective is in accordance with the 2010 policy of the Ministry of Health of Indonesian Government about scientification of Jamu. Thus, it is required to systemize the formulations and develop basic scientific principles of Jamu to meet the requirement of Indonesian Healthcare System. Afendi et al. initiated and conducted scientific analysis of Jamu for finding the correlation between plants, Jamu, and their efficacy using statistical methods [6–8]. They used Biplot, partial least squares (PLS), and bootstrapping methods to summarize the data and also focused on prediction of Jamu formulations. These methods give a good understanding about relationship between plants, Jamu, and their efficacy. Among 465 plants used in 3138 Jamu, 190 plants were shown to be effective for at least one efficacy and these plants were considered to be the main ingredients of Jamu. The other 275 plants are considered to be supporting ingredients in Jamu because their efficacy has not been established yet.Network biology can be defined as the study of the network representations of molecular interactions, both to analyze such networks and to use them as a tool to make biological predictions [9]. This study includes modelling, analysis, and visualizations, which holds important task in life science today [10]. Network analysis has been increasingly utilized in interpreting high throughput data on omics information, including transcriptional regulatory networks [11], coexpression networks [12], and protein-protein interactions [13]. We can easily describe relationship between entities in the network and also concentrate on part of the network consisting of important nodes or edges. These advantages can be adopted for analyzing medicinal usage of plants in Jamu and diseases. Network analysis provides information about groups of Jamu that are closely related to each other in terms of ingredient similarity and thus allows precise investigation to relate plants to diseases. On the other hand, multivariate statistical methods such as PLS can assign plants to efficacy by global linear modeling of the Jamu ingredients and efficacy. However, there is still lack of appropriate network based methods to learn how and why many plants are grouped in certain Jamu formula and the combination rule embedding numerous Jamu formulas.It is needed to explore the relationship between Indonesian herbal plants used in Jamu medicines and the diseases which are treated using Jamu medicines. When effectiveness of a plant against a disease is firmly established, then further analysis about that plant can be proceeded to molecular level to pinpoint the drug targets. The present study developed a network based approach for prediction of plant-disease relations. We utilized the Jamu data from the KNApSAcK database. A Jamu network was constructed based on the similarity of their ingredients and then Jamu clusters were generated using the network clustering algorithm DPClusO [14, 15]. Plant-disease relations were then predicted by determining the dominant diseases and plants associated with selected Jamu clusters.


## 2. Methods

### 2.1. Concept of the Methodology

Jamu medicines consist of combination of medicinal plants and are used to treat versatile diseases. In this work we exploit the ingredient similarity between Jamu medicines to predict plant-disease relations. The concept of the proposed method is depicted in Figure1. In step 1 a network is constructed where a node is a Jamu medicine and an edge represents high ingredient similarity between the corresponding Jamu pair. In Figure 1, the nodes of the same color indicate the Jamu medicines used for the same disease. The similarity is represented by Pearson correlation coefficient [16, 17]; that is,
(1)
corr
(
X
,
Y
)
=
∑
i
=
1
l
(
x
i
-
x
¯
)
(
y
i
-
y
¯
)
∑
i
=
1
l
(
x
i
-
x
¯
)
2
∑
i
=
1
l
(
y
i
-
y
¯
)
2
,
where x
i is the weight of plant-i in Jamu X, y
i is the weight of plant-i in Jamu Y, x
¯ is mean of Jamu X, and y
¯ is mean of Jamu Y. The higher similarity between Jamu pairs the higher the correlation value. In the present study, x
i and y
i are assigned as 1 or 0 in cases the ith plant is, respectively, included or not included in the formula. Under such condition, Pearson correlation corresponds to fourfold point correlation coefficient; that is,
(2)
corr
(
X
,
Y
)
=
a
d
-
b
c
(
a
+
b
)
(
a
+
c
)
(
b
+
d
)
(
c
+
d
)
,
where a, b, c, and d represent the numbers of plants included in both X and Y, in only X, in only Y, and in neither X nor Y, respectively.Figure 1
Concept of the methodology: network construction based on ingredient similarity between individual Jamu medicines, network clustering, and classification of medicinal plants to dominant disease.In step 2 the Jamu clusters are generated using network clustering algorithm DPClusO. DPClusO can generate clusters characterized by high density and identified by periphery; that is, the Jamu medicines belonging to a cluster are highly cohesive and separated by a natural boundary. Such clusters contain potential information about plant-disease relations.In step 3 we assess disease-dominant clusters based on matching score represented by the following equation:(3)
matching
score
=
number
of
Jamu
belonging
to
the
same
disease
total
number
of
Jamu
in
the
cluster
.
Matching score of a cluster is the ratio of the highest number of Jamu associated with a single disease to the total number of Jamu in the cluster. We assign a disease to a cluster for which the matching score is greater than a threshold value. In step 4, we determine the frequency of plants associated with a cluster if and only if a disease is assigned to it in the previous step. The highest frequency plant associated to a cluster is considered to be related to the disease assigned to that cluster. True positive rates (TPR) or sensitivity was used to evaluate resulting plants. TPR is the proportion of the true positive predictions out of all the true predictions, defined by the following formula [18]:
(4)
TPR
=
TP
TP
+
FN
,
where true positive (
TP
) is the number of correctly classified and false negative (
FN
) is the number of incorrectly rejected entities. We refer to the proposed method as supervised clustering because after generation of the clusters we narrow down the candidate clusters for further analysis based on supervised learning and thus improve the accuracy of prediction of the proposed method.


## 2.1. Concept of the Methodology

Jamu medicines consist of combination of medicinal plants and are used to treat versatile diseases. In this work we exploit the ingredient similarity between Jamu medicines to predict plant-disease relations. The concept of the proposed method is depicted in Figure1. In step 1 a network is constructed where a node is a Jamu medicine and an edge represents high ingredient similarity between the corresponding Jamu pair. In Figure 1, the nodes of the same color indicate the Jamu medicines used for the same disease. The similarity is represented by Pearson correlation coefficient [16, 17]; that is,
(1)
corr
(
X
,
Y
)
=
∑
i
=
1
l
(
x
i
-
x
¯
)
(
y
i
-
y
¯
)
∑
i
=
1
l
(
x
i
-
x
¯
)
2
∑
i
=
1
l
(
y
i
-
y
¯
)
2
,
where x
i is the weight of plant-i in Jamu X, y
i is the weight of plant-i in Jamu Y, x
¯ is mean of Jamu X, and y
¯ is mean of Jamu Y. The higher similarity between Jamu pairs the higher the correlation value. In the present study, x
i and y
i are assigned as 1 or 0 in cases the ith plant is, respectively, included or not included in the formula. Under such condition, Pearson correlation corresponds to fourfold point correlation coefficient; that is,
(2)
corr
(
X
,
Y
)
=
a
d
-
b
c
(
a
+
b
)
(
a
+
c
)
(
b
+
d
)
(
c
+
d
)
,
where a, b, c, and d represent the numbers of plants included in both X and Y, in only X, in only Y, and in neither X nor Y, respectively.Figure 1
Concept of the methodology: network construction based on ingredient similarity between individual Jamu medicines, network clustering, and classification of medicinal plants to dominant disease.In step 2 the Jamu clusters are generated using network clustering algorithm DPClusO. DPClusO can generate clusters characterized by high density and identified by periphery; that is, the Jamu medicines belonging to a cluster are highly cohesive and separated by a natural boundary. Such clusters contain potential information about plant-disease relations.In step 3 we assess disease-dominant clusters based on matching score represented by the following equation:(3)
matching
score
=
number
of
Jamu
belonging
to
the
same
disease
total
number
of
Jamu
in
the
cluster
.
Matching score of a cluster is the ratio of the highest number of Jamu associated with a single disease to the total number of Jamu in the cluster. We assign a disease to a cluster for which the matching score is greater than a threshold value. In step 4, we determine the frequency of plants associated with a cluster if and only if a disease is assigned to it in the previous step. The highest frequency plant associated to a cluster is considered to be related to the disease assigned to that cluster. True positive rates (TPR) or sensitivity was used to evaluate resulting plants. TPR is the proportion of the true positive predictions out of all the true predictions, defined by the following formula [18]:
(4)
TPR
=
TP
TP
+
FN
,
where true positive (
TP
) is the number of correctly classified and false negative (
FN
) is the number of incorrectly rejected entities. We refer to the proposed method as supervised clustering because after generation of the clusters we narrow down the candidate clusters for further analysis based on supervised learning and thus improve the accuracy of prediction of the proposed method.


## 3. Result and Discussion

### 3.1. Construction and Comparison of Jamu and Random Networks

We used the same number of Jamu formulas from previous research [6], 3138 Jamu formulas, and the set union of all formulas consists of 465 plants. We assigned 3138 Jamu formulas to 116 diseases of International Classification of Diseases (ICD) version 10 from World Health Organization (WHO, Table 1) [19]. Those 116 diseases are mapped to 18 classes of disease, which contains 16 classes of disease from National Center for Biotechnology Information (NCBI) [20] and 2 additional classes. Table 2 shows distribution of 3138 Jamu into 18 classes of disease. According to this classification, most Jamu formulas are useful for relieving muscle and bone, nutritional and metabolic diseases, and the digestive system. Furthermore, there is no Jamu formula classified into glands and hormones and neonatal disease classes. We excluded 4 Jamu formulas which are used to treat fever in the evaluation process because this symptom is very general and almost appeared in all disease classes. Jamu-plant-disease relations can be represented using 2 matrices: first matrix is Jamu-plant relation with dimension 3138
×
465 and the second matrix is Jamu-disease relation with dimension 3138
×
18.Table 1
List of diseases using International Classification of Diseases ver. 10 (class of disease IDs correspond to Table2).
ID
Disease
Class of disease
1
Abdominal pain
3
2
Abdominal pain, diarrhea
3
3
Acne
16
4
Acne, skin problems (cosmetics)
16
5
Amenorrhoea, dysmenorrhea
6
6
Amenorrhoea, irregular menstruation
6
7
Anaemia
1
8
Appendicitis, urinary tract infection, tonsillitis
3
9
Arthralgia
11
10
Arthralgia, arthritis
11
11
Asthma
15
12
Benign prostatic hyperplasia (Bph)
10
13
Breast disorder
6
14
Bromhidrosis
16
15
Bronchitis
15
16
Cancer
2
17
Cancer pain
2
18
Cancer, inflammation
2
19
Colic abdomen, bloating (in infant)
3
20
Common cold
15
21
Common cold, dyspepsia, insect bites
15, 3, 16
22
Common cold, influenza
15
23
Cough
15
24
Degenerative disease
14
25
Dermatitis, urticaria, erythema
16
26
Diabetes
14
27
Diabetic gangrene
16
28
Diarrhea
3
29
Diarrhea, abdominal pain
3
30
Diseases of the eye
5
31
Disorders in pregnancy
6
32
Dysmenorrhea
6
33
Dysmenorrhea, irregular menstruation
6
34
Dysmenorrhea, menstrual syndrome
6
35
Dyspepsia
3
36
Dyspnoea
15
37
Dyspnoea, cough, orthopnoea
15
38
Fatigue
11
39
Fatigue, anaemia, loss appetite
1
40
Fatigue, lack of sexual function
6
41
Fatigue, low back pain
11
42
Fatigue, myalgia, arthralgia
11
43
Fatigue, osteoarthritis
11
44
Fertility problem
6, 10
45
Fever
0
46
Gastritis, gastric ulcer
3
47
Haemorrhoids
1
48
Headache
13
49
Heart diseases
8
50
Heartburn
3, 8
51
Hepatitis, other diseases of liver
3
52
Hypercholesterolaemia
14
53
Hypertension
8
54
Hypertension, diabetes
14
55
Hypertension, hypercholesterolaemia
14
56
Hyperuricemia
1
57
Immunodefficiency
9
58
Indigestion (K.30)
3
59
Indigestion, lose appetite
3
60
Infertility
6, 10
61
Irregular menstruation, menstruation syndrome
6
62
Kidney diseases
17
63
Lactation problems
6
64
Leukorrhoea (Vaginalis)
6
65
Leukorrhoea (Vaginalis), dysmenorrhoea
6
66
Lose appetite
3
67
Lose appetite, underweight
14
68
Low back pain, myalgia, arthralgia
11
69
Low back pain, myalgia, constipation
11
70
Low back pain, urinary tract infection
17
71
Lung diseases
15
72
Malaise and Fatigue
11
73
Malaise and Fatigue, Constipation
11
74
Malaise and Fatigue, Fertility Problems
10, 11
75
Malaise and Fatigue, Low Back Pain
11
76
Malaise and Fatigue, Sexual Dysfunction
11, 6, 10
77
Malaise and Fatigue, Skin Problems (Cosmetics)
16
78
Malaria, anaemia
1
79
Meno-metrorrhagia
6
80
Menopausal syndrome
6
81
Menopause/menstrual syndrome, leukorrhoea (vaginalis)
6
82
Menstrual syndrome
6
83
Menstrual syndrome, fatigue
6
84
Migraine
13
85
Mood disorder
18
86
Myalgia, arthralgia
11
87
Nausea/vomiting of pregnancy
6
88
Osteoarthritis
11
89
Osteoarthritis, fatigue
11
90
Overweight, obesity
14
91
Paralysis
13
92
Post partum syndrome
6
93
Prevent from overweight
14
94
Respiratory infection due to smoking
15
95
Respiratory tract infection
15
96
Rheumatoid arthritis, gout
11
97
Secondary amenorrhea
6
98
Secondary amenorrhea, irregular menstruation
6
99
Sexual dysfunction, fatigue
6, 10
100
Skin diseases
16
101
Skin problems (cosmetics)
16
102
Sleeping and Mood Disorders
18
103
Sleeping disorders
18
104
Stomatitis
3
105
Stomatitis, gingivitis, tonsilitis
3
106
Stone in kidney (N20.0)
17
107
Stone in kidney (N20.0), urinary bladder stone (N21.0)
17
108
Tonsilitis
4
109
Tonsilofaringitis
4
110
Toothache
13
111
Typhoid, dyspepsia
3
112
Ulcer of anus and rectum
3
113
Underweight, lose appetite
3
114
Urinary tract infection (urethritis)
17
115
Vaginal discharges
6
116
Vaginal diseases
6Table 2
Distribution of Jamu formulas according to 18 classes of disease (classes of diseases are determined by NCBI in ID1 to ID16 and by the present study in ID17 and ID18 represented by asterisks in Ref. columns).
ID
Class of disease (NCBI)
Ref.
Number of Jamu
Percentage
1
Blood and lymph diseases
NCBI
201
6.41
2
Cancers
NCBI
32
1.02
3
The digestive system
NCBI
457
14.56
4
Ear, nose, and throat
NCBI
2
0.06
5
Diseases of the eye
NCBI
1
0.03
6
Female-specific diseases
NCBI
382
12.17
7
Glands and hormones
NCBI
0
—
8
The heart and blood vessels
NCBI
57
1.82
9
Diseases of the immune system
NCBI
22
0.70
10
Male-specific diseases
NCBI
17
0.54
11
Muscle and bone
NCBI
649
20.68
12
Neonatal diseases
NCBI
0
—
13
The nervous system
NCBI
32
1.02
14
Nutritional and metabolic diseases
NCBI
576
18.36
15
Respiratory diseases
NCBI
313
9.97
16
Skin and connective tissue
NCBI
163
5.19
17
The urinary system
*
90
2.87
18
Mental and behavioral disorders
*
21
0.67
The number of Jamu classified into multiple disease classes
119
3.79
The number of Jamu unclassified
4
0.13
Total Jamu formulas
3138
100.00After completion of data acquisition process, we calculated the similarity between Jamu pairs using correlation measure. The similarity measures between Jamu pairs were determined based on their ingredients. Corresponding toK (3138 in present case) Jamu formulas, there can be maximum (
K
×
(
K
-
1
)
/
2
) = (
3138
×
(
3137
/
2
)
) = 4,921,953 Jamu pairs. We sorted the Jamu pairs based on correlation value using descending order and selected top-n (0.7%, 0.5%, and 0.3%) pairs of Jamu formula to create 3 sets of Jamu pairs. The number of Jamu pairs for 0.7%, 0.5%, and 0.3% datasets is 34,454 pairs, 24,610 pairs, and 14,766 pairs and the corresponding minimum correlation values are 0.596, 0.665, and 0.718, respectively. The three datasets of Jamu pairs can be regarded as three undirected networks (step 1 in Figure 1) consisting of 2779, 2496, and 2085 Jamu formulas, respectively (Table 3). Figure 2 shows visualization of 0.7% Jamu networks using Cytoscape Spring Embedded layout. We verified that the degree distributions of the Jamu networks are somehow close to those of scale-free networks, that is, roughly are of power law type. However, in the high-degree region the power law structure is broken (Figure 3). Nearly accurate relation of power laws between medicinal herbs and the number of formulas utilizing them was observed in Jamu system but not in Kampo (Japanese crude drug system) [4]. The difference of formulas between Jamu and Kampo can be explained by herb selection by medicinal researchers based on the optimization process of selection [4]. Thus, the broken structure of power law corresponding to Jamu networks is associated with the fact that selection of Jamu pairs based on ingredient correlation leads to nonrandom selection. We also constructed random networks according to Erdős-Rényi (ER) model [21], Barabási-Albert (BA) model [22], and Vazquez’s Connecting Nearest Neighbor (CNN) model [23] of the same size corresponding to each of the real Jamu network. We used Cytoscape Network Analyzer plugin [24] and R software for analyzing the characteristics of both the Jamu and the random networks.Table 3
Statistics of three datasets.
Parameters
0.7%
0.5%
0.3%
Network statistics
Total pairs
34,454
24,610
14,766
Minimum correlation
0.596
0.665
0.718
Number of Jamu formulas
2,779
2,496
2,085
Average degree
24.8
19.7
14.2
(Random network: ER)
(
24.8
±
0.0
)
(
19.7
±
0.0
)
(
14.2
±
0.0
)
(Random network: BA)
(
24.7
±
0.1
)
(
19.7
±
0.1
)
(
14.1
±
0.1
)
(Random network: CNN)
(
24.7
±
0.4
)
(
19.7
±
0.4
)
(
14.0
±
0.4
)
Clustering coefficient
0.521
0.520
0.540
(Random network: ER)
(
0.009
±
0.000
)
(
0.008
±
0.000
)
(
0.007
±
0.000
)
(Random network: BA)
(
0.030
±
0.001
)
(
0.028
±
0.001
)
(
0.026
±
0.001
)
(Random network: CNN)
(
0.246
±
0.008
)
(
0.239
±
0.008
)
(
0.233
±
0.010
)
Number of connected components
69
119
254
(Random networks: ER, BA, CNN)
(1)
(1)
(1)
Network diameter
15
17
20
(Random network: ER)
(
4.0
±
0.0
)
(
4.0
±
0.0
)
(
5.0
±
0.0
)
(Random network: BA)
(
10.8
±
0.8
)
(
11.2
±
1.5
)
(
10.8
±
0.9
)
(Random network: CNN)
(
14.6
±
1.9
)
(
14.1
±
1.4
)
(
14.7
±
1.3
)
Network density
0.008
0.008
0.007
(Random network: ER)
(
0.009
±
0.000
)
(
0.008
±
0.000
)
(
0.007
±
0.000
)
(Random network: BA)
(
0.009
±
0.000
)
(
0.008
±
0.000
)
(
0.007
±
0.000
)
(Random network: CNN)
(
0.009
±
0.000
)
(
0.008
±
0.000
)
(
0.007
±
0.000
)
DPClusO
Total number of clusters
1,746
1,411
938
Number of clusters with more than 2 Jamu
1,296
873
453
(%)
(74.2)
(61.9)
(48.3)
Number of Jamu formulas in the biggest cluster
118
104
89Figure 2
The network consisting of 0.7% Jamu pairs (correlation value above or equal to 0.596).Figure 3
Degree distributions of three Jamu networks roughly follow power law. Thex-axis corresponds to the log of degree of a node in the Jamu network and the y-axis corresponds to the log of the number of Jamu.We determined five statistical indexes, that is, average degree, clustering coefficient, number of connected component, network diameter, and network density of each Jamu network and also of each random network. The clustering coefficientC
n of a node n is defined as C
n
=
2
e
n
/
(
k
n
(
k
n
-
1
)
), where k
n is the number of neighbors of n and e
n is the number of connected pairs between all neighbors of n. The network diameter is the largest distance between any two nodes. If a network is disconnected, its diameter is the maximum of all diameters of its connected components. A network’s density is the ratio of the number of edges in the network over the total number of possible edges between all pairs of nodes (which is n
(
n
-
1
)
/
2, where n is the number of vertices, for an undirected graph). The average number of neighbors and the network density are the same for the real and random networks of the same size as it is shown in Table 3. In case of 0.7% and 0.5% real networks, the clustering coefficient is roughly the same and in case of 0.3% the clustering coefficient is somewhat larger. The number of connected components and the diameter of the Jamu networks gradually decrease as the network grows bigger by addition of more nodes and edges.Very different values corresponding to clustering coefficient, connected component, and network diameter imply that the Jamu networks are quite different from all 3 types of random networks. The differences between Jamu networks and ER random networks are the largest. Random networks constructed based on other two models are also substantially different from Jamu networks. Based on the fact that the random networks constructed based on all three types of models are different from the Jamu networks, it can be concluded that structure of Jamu networks is reasonably biased and thus might contain certain information about plant-disease relations. Specially, much higher value corresponding to clustering coefficient indicates that there are clusters in the networks worthy to be investigated. To extract clusters from the Jamu networks (step 2 in Figure1) we applied DPClusO network clustering algorithm [14] to generate overlapping clusters based on density and periphery tracking.


### 3.2. Supervised Clustering Based on DPClusO

DPClusO is a general-purpose clustering algorithm and useful for finding overlapping cohesive groups in an undirected simple graph for any type of application. It ensures coverage and performs robustly in case of random addition, removal, and rearrangement of edges in protein-protein interaction (PPI) networks [14]. While applying DPClusO, the parameter values of density and cluster property that we used in this experiment are 0.9 and 0.5, respectively [15]. Table 3 shows the summary of clustering result by DPClusO. Because clusters consisting of two Jamu formulas are trivial clusters, for the next steps we only use clusters each of which consists of 3 or more Jamu formulas. The number of total clusters increases along with the larger dataset, although the threshold correlation between Jamu pairs decreases. We evaluated the clustering result using matching score to determine dominant disease for every cluster (step 3 in Figure 1). Matching score of a cluster is the ratio of the highest number of Jamu associated with the same disease to the total number of Jamu in the cluster. Thus matching score is a measure to indicate how strongly a disease is associated to a cluster. Figure 4 shows the distribution of the clusters with respect to matching score from three datasets. All datasets have the highest frequency of clusters at matching score >0.9 and overall most of the clusters have higher matching score, which means most of the DPClusO generated clusters can be confidently related to a dominant disease. Furthermore the number of clusters with matching score >0.9 is remarkably larger compared to the same in other ranges of matching score in case of the 0.3% dataset (Figure 4(c)). If we compare the ratio of frequency of clusters at matching score >0.9 for every dataset, the 0.3% dataset has the highest ratio with 40.84% (of 453), compared to 29.67% (of 873) and 21.91% (of 1296), in case of 0.5% and 0.7% datasets, respectively. Thus, the most reliable species to disease relations can be predicted at matching score >0.9 corresponding to the clusters generated from 0.3% dataset.Distribution of clusters based on matching score.
(a)
0.7%
(b)
0.5%
(c)
0.3%Figure5(a) shows the success rate for all 3 datasets with respect to threshold matching scores. Success rate is defined as the ratio of the number of clusters with matching score larger than the threshold to the total number of clusters. As expected it tends to produce lower success rate if we decrease correlation value to create the datasets. However more clusters are generated and more information can be extracted when we lower the threshold correlation value. The success rate increases rapidly as the matching score decreases from 0.9 to 0.6 and after that the slope of increase of success rate decreases. Therefore in this study we empirically decide 0.6 as the threshold matching score to predict plant-disease relations.(a) Success rate and (b) number of predicted plants with respect to matching score thresholds.
(a)
(b)


### 3.3. Assignment of Plants to Disease

By using DPClusO resulting clusters, we assigned plants to classes of disease. Based on a threshold matching score we assigned dominant disease to a cluster. Then we assign a plant to a cluster by way of analyzing the ingredients of the Jamu formulas belonging to that cluster and determining the highest frequency plant, that is, the plant that is used for maximum number Jamu belonging to that cluster (step 4 in Figure1). Thus we assign a disease and a plant to each cluster having matching score greater than a threshold. Our hypothesis is that the disease and the plant assigned to the same cluster are related.The total number of assigned plants depends on matching score value. Figure5(b) shows the number of predicted plants that can be assigned to diseases in the context of matching score. With higher matching score value, the number of predicted plants assigned to classes of disease is supposed to remain similar or decrease but the reliability of prediction increases. In Figure 5(b) a sudden change in the number of predicted plants is seen at matching score 0.6 which we consider as empirical threshold in this work. Based on the 0.7% dataset, the largest number of plants (135 plants, Table 4) was assigned to diseases. There are 63 plants assigned to only one class of disease, whereas the other 72 plants are assigned to at least two or more classes of disease (Figure 6).Table 4
List of plants assigned to each disease.
Number
Plants  name
Hit-miss  status
A.  Disease:  blood  and  lymph diseases
1
Tamarindus  indica
Hit
*
2
Allium  sativum
Hit
*
3
Tinospora  tuberculata
Hit
*
4
Piper  retrofractum
Hit
5
Syzygium  aromaticum
Hit
*
6
Bupleurum  falcatum
Hit
7
Graptophyllum  pictum
Hit
8
Plantago  major
Hit
9
Zingiber  officinale
Hit
*
10
Cinnamomum
burmannii
Hit
*
11
Soya  max
Miss
*
12
Kaempferia  galanga
Hit
13
Curcuma  longa
Hit
*
14
Piper  nigrum
Hit
15
Zingiber  aromaticum
Hit
*
16
Phyllanthus  urinaria
Hit
*
17
Oryza  sativa
Hit
18
Myristica  fragrans
Hit
*
19
Alstonia  scholaris
Hit
*
20
Syzygium  polyanthum
Miss
21
Andrographis  paniculata
Hit
*
22
Sida  rhombifolia
Miss
23
Cyperus  rotundus
Hit
24
Sonchus  arvensis
Miss
25
Curcuma  aeruginosa
Hit
*
26
Curcuma  xanthorrhiza
Hit
B.  Disease:  cancers
1
Catharanthus  roseus
Hit
C.  Disease:  the  digestive  system
1
Foeniculum  vulgare
Hit
2
Glycyrrhiza  uralensis
Hit
*
3
Imperata  cylindrica
Hit
4
Zingiber  purpureum
Hit
*
5
Physalis  peruviana
Hit
6
Punica  granatum
Hit
*
7
Echinacea  purpurea
Hit
8
Zingiber  officinale
Hit
*
9
Psidium  guajava
Hit
10
Baeckea  frutescens
Hit
*
11
Amomum  compactum
Hit
12
Cinnamomum
burmannii
Hit
*
13
Melaleuca  leucadendra
Hit
14
Caesalpinia  sappan
Hit
*
15
Parkia  roxburghii
Hit
16
Rheum  tanguticum
Hit
17
Kaempferia  galanga
Hit
18
Coriandrum  sativum
Hit
19
Curcuma  longa
Hit
20
Zingiber  aromaticum
Hit
21
Phyllanthus  urinaria
Hit
22
Myristica  fragrans
Hit
23
Hydrocotyle  asiatica
Hit
*
24
Carica  papaya
Hit
25
Mentha  arvensis
Hit
26
Lepiniopsis  ternatensis
Hit
27
Helicteres  isora
Hit
28
Andrographis  paniculata
Hit
29
Symplocos  odoratissima
Hit
30
Schisandra  chinensis
Hit
31
Blumea  balsamifera
Hit
32
Silybum  marianum
Hit
*
33
Cinnamomum
sintoc
Hit
34
Elephantopus  scaber
Hit
35
Curcuma  aeruginosa
Hit
36
Kaempferia  pandurata
Hit
37
Curcuma  xanthorrhiza
Hit
38
Curcuma  mangga
Hit
*
39
Curcuma  zedoaria
Hit
40
Daucus  carota
Hit
*
41
Matricaria  chamomilla
Hit
*
42
Cymbopogon  nardus
Hit
*
D.  Disease:  female-specific  diseases
1
Foeniculum  vulgare
Hit
2
Imperata  cylindrica
Hit
3
Tamarindus  indica
Hit
4
Pluchea  indica
Hit
*
5
Piper  retrofractum
Hit
6
Punica  granatum
Hit
7
Uncaria  rhynchophylla
Hit
8
Zingiber  officinale
Hit
9
Guazuma  ulmifolia
Hit
*
10
Nigella  sativa
Hit
11
Terminalia  bellirica
Hit
12
Baeckea  frutescens
Hit
13
Phaseolus  radiatus
Hit
14
Amomum  compactum
Hit
*
15
Sauropus  androgynus
Hit
16
Usnea  misaminensis
Hit
17
Cinnamomum
burmannii
Hit
18
Melaleuca  leucadendra
Hit
19
Parameria  laevigata
Hit
20
Parkia  roxburghii
Hit
21
Piper  cubeba
Hit
22
Kaempferia  galanga
Hit
23
Coriandrum  sativum
Hit
24
Kaempferia  angustifolia
Hit
25
Curcuma  longa
Hit
26
Zingiber  aromaticum
Hit
27
Languas  galanga
Hit
28
Galla  lusitania
Hit
29
Quercus  lusitanica
Hit
30
Hydrocotyle  asiatica
Hit
31
Areca  catechu
Hit
32
Lepiniopsis  ternatensis
Hit
33
Helicteres  isora
Hit
*
34
Piper  betle
Hit
35
Elephantopus  scaber
Hit
*
36
Kaempferia  pandurata
Hit
37
Curcuma  xanthorrhiza
Hit
38
Sesbania  grandiflora
Hit
E.  Disease:  the  heart  and  blood  vessels
1
Allium  sativum
Hit
2
Curcuma  longa
Hit
*
3
Morinda  citrifolia
Hit
*
4
Homalomena  occulta
Hit
*
5
Hydrocotyle  asiatica
Hit
6
Alstonia  scholaris
Hit
*
7
Syzygium  polyanthum
Miss
*
8
Andrographis  paniculata
Hit
*
9
Apium  graveolens
Miss
10
Imperata  cylindrica
Hit
F.  Disease:  male-specific  diseases
1
Cucurbita  pepo
Miss
2
Serenoa  repens
Miss
3
Baeckea  frutescens
Hit
4
Phaseolus  radiatus
Hit
5
Curcuma  longa
Hit
6
Elephantopus  scaber
Hit
G.  Disease:  muscle  and  bone
1
Foeniculum  vulgare
Hit
2
Clausena  anisum-olens
Hit
*
3
Zingiber  purpureum
Hit
4
Allium  sativum
Hit
5
Strychnos  ligustrina
Hit
6
Tinospora  tuberculata
Hit
*
7
Piper  retrofractum
Hit
8
Syzygium  aromaticum
Hit
9
Cola  nitida
Hit
*
10
Ginkgo  biloba
Hit
*
11
Panax  ginseng
Hit
12
Equisetum  debile
Hit
*
13
Zingiber  officinale
Hit
14
Ganoderma  lucidum
Hit
15
Nigella  sativa
Hit
16
Terminalia  bellirica
Hit
*
17
Baeckea  frutescens
Hit
*
18
Amomum  compactum
Hit
19
Cinnamomum
burmannii
Hit
20
Melaleuca  leucadendra
Hit
21
Parameria  laevigata
Hit
*
22
Psophocarpus  tetragonolobus
Hit
*
23
Parkia  roxburghii
Hit
24
Piper  cubeba
Hit
*
25
Kaempferia  galanga
Hit
26
Coriandrum  sativum
Hit
27
Cola  acuminata
Hit
28
Coffea  arabica
Hit
29
Orthosiphon  stamineus
Hit
30
Curcuma  longa
Hit
31
Piper  nigrum
Hit
32
Alpinia  galanga
Hit
33
Vitex  trifolia
Hit
34
Zingiber  amaricans
Hit
*
35
Zingiber  zerumbet
Hit
36
Zingiber  aromaticum
Hit
37
Languas  galanga
Hit
38
Massoia  aromatica
Hit
39
Morinda  citrifolia
Hit
40
Carum  copticum
Hit
*
41
Panax  pseudoginseng
Hit
*
42
Oryza  sativa
Hit
43
Myristica  fragrans
Hit
44
Pandanus  amaryllifolius
Hit
45
Eurycoma  longifolia
Hit
46
Hydrocotyle  asiatica
Hit
47
Areca  catechu
Hit
*
48
Mentha  arvensis
Hit
*
49
Lepiniopsis  ternatensis
Hit
50
Pimpinella  pruatjan
Hit
51
Andrographis  paniculata
Hit
52
Blumea  balsamifera
Hit
53
Cymbopogon  nardus
Hit
54
Sida  rhombifolia
Hit
55
Cinnamomum
sintoc
Hit
56
Piper  betle
Hit
*
57
Talinum  paniculatum
Hit
58
Elephantopus  scaber
Hit
59
Cyperus  rotundus
Hit
60
Curcuma  aeruginosa
Hit
61
Kaempferia  pandurata
Hit
*
62
Curcuma  xanthorrhiza
Hit
63
Tribulus  terrestris
Hit
64
Corydalis  yanhusuo
Hit
65
Pausinystalia  yohimbe
Hit
H.  Disease:  nutritional  and metabolic  diseases
1
Foeniculum  vulgare
Hit
2
Glycyrrhiza  uralensis
Hit
3
Zingiber  purpureum
Hit
4
Allium  sativum
Hit
5
Tinospora  tuberculata
Hit
6
Pandanus  conoideus
Hit
7
Syzygium  aromaticum
Hit
8
Punica  granatum
Hit
9
Zingiber  officinale
Hit
10
Guazuma  ulmifolia
Hit
11
Nigella  sativa
Hit
12
Amomum  compactum
Hit
*
13
Cinnamomum
burmannii
Hit
14
Parameria  laevigata
Hit
15
Caesalpinia  sappan
Hit
16
Soya  max
Hit
*
17
Cocos  nucifera
Hit
18
Rheum  tanguticum
Hit
19
Piper  cubeba
Hit
*
20
Murraya  paniculata
Hit
21
Kaempferia  galanga
Hit
*
22
Coffea  arabica
Hit
*
23
Orthosiphon  stamineus
Hit
24
Curcuma  longa
Hit
25
Piper  nigrum
Hit
*
26
Zingiber  aromaticum
Hit
27
Aloe  vera
Hit
28
Phaleria  papuana
Hit
29
Galla  lusitania
Hit
30
Quercus  lusitanica
Hit
31
Morinda  citrifolia
Hit
32
Myristica  fragrans
Hit
*
33
Momordica  charantia
Hit
34
Areca  catechu
Hit
35
Lepiniopsis  ternatensis
Hit
36
Alstonia  scholaris
Hit
37
Hibiscus  sabdariffa
Hit
38
Laminaria  japonica
Hit
39
Syzygium  polyanthum
Hit
40
Andrographis  paniculata
Hit
41
Sindora  sumatrana
Hit
*
42
Cassia  angustifolia
Hit
43
Woodfordia  floribunda
Hit
44
Piper  betle
Hit
45
Spirulina
Hit
46
Stevia  rebaudiana
Hit
47
Theae  sinensis
Hit
48
Sonchus  arvensis
Hit
49
Curcuma  heyneana
Hit
50
Curcuma  aeruginosa
Hit
51
Kaempferia  pandurata
Hit
*
52
Curcuma  xanthorrhiza
Hit
53
Curcuma  zedoaria
Hit
*
54
Olea  europaea
Hit
I.  Disease  respiratory  diseases
1
Foeniculum  vulgare
Hit
2
Clausena  anisum-olens
Hit
3
Glycyrrhiza  uralensis
Hit
4
Zingiber  purpureum
Hit
5
Piper  retrofractum
Hit
*
6
Syzygium  aromaticum
Hit
7
Gaultheria  punctata
Hit
8
Panax  ginseng
Hit
9
Equisetum  debile
Hit
*
10
Zingiber  officinale
Hit
11
Citrus  aurantium
Hit
*
12
Nigella  sativa
Hit
*
13
Amomum  compactum
Hit
14
Cinnamomum
burmannii
Hit
15
Melaleuca  leucadendra
Hit
16
Parkia  roxburghii
Hit
17
Cocos  nucifera
Hit
18
Piper  cubeba
Hit
19
Kaempferia  galanga
Hit
20
Coriandrum  sativum
Hit
21
Curcuma  longa
Hit
22
Piper  nigrum
Hit
23
Zingiber  aromaticum
Hit
24
Languas  galanga
Hit
25
Mentha  piperita
Hit
26
Oryza  sativa
Hit
*
27
Myristica  fragrans
Hit
28
Pandanus  amaryllifolius
Hit
*
29
Hydrocotyle  asiatica
Hit
*
30
Mentha  arvensis
Hit
31
Lepiniopsis  ternatensis
Hit
32
Helicteres  isora
Hit
33
Blumea  balsamifera
Hit
34
Cymbopogon  nardus
Hit
35
Piper  betle
Hit
36
Curcuma  xanthorrhiza
Hit
37
Salix  alba
Hit
*
38
Matricaria  chamomilla
Miss
*
J.  Disease:  skin  and  connective  tissue
1
Strychnos  ligustrina
Hit
2
Merremia  mammosa
Hit
*
3
Piper  retrofractum
Hit
*
4
Santalum  album
Hit
5
Zingiber  officinale
Hit
*
6
Citrus  aurantium
Hit
7
Citrus  hystrix
Hit
8
Cassia  siamea
Hit
9
Cocos  nucifera
Hit
10
Trigonella  foenum-graecum
Hit
11
Orthosiphon  stamineus
Hit
12
Curcuma  longa
Hit
13
Vetiveria  zizanioides
Hit
14
Aloe  vera
Hit
15
Rosa  chinensis
Hit
16
Jasminum  sambac
Hit
17
Phyllanthus  urinaria
Hit
18
Mentha  piperita
Hit
19
Oryza  sativa
Hit
20
Myristica  fragrans
Hit
*
21
Hydrocotyle  asiatica
Hit
22
Lepiniopsis  ternatensis
Hit
23
Alstonia  scholaris
Hit
24
Andrographis  paniculata
Hit
25
Cymbopogon  nardus
Hit
26
Piper  betle
Hit
27
Theae  sinensis
Hit
28
Curcuma  heyneana
Hit
29
Kaempferia  pandurata
Hit
*
30
Curcuma  xanthorrhiza
Hit
31
Melaleuca  leucadendra
Hit
32
Matricaria  chamomilla
Miss
*
K.  Disease:  the  urinary  system
1
Foeniculum  vulgare
Hit
*
2
Imperata  cylindrica
Hit
*
3
Strychnos  ligustrina
Hit
*
4
Plantago  major
Hit
5
Zingiber  officinale
Hit
*
6
Cinnamomum
burmannii
Hit
*
7
Strobilanthes  crispus
Hit
8
Kaempferia  galanga
Hit
*
9
Orthosiphon  stamineus
Hit
10
Phyllanthus  urinaria
Hit
11
Blumea  balsamifera
Hit
*
12
Sonchus  arvensis
Hit
13
Curcuma  xanthorrhiza
Hit
*indicates that plant will not assigned if we use matching score >0.7.Figure 6
Distribution of 135 plants assigned based on 0.7% dataset with respect to the number of diseases they are assigned to.


### 3.4. Evaluation of the Supervised Clustering Based on DPClusO

We used previously published results [6] as gold standard to evaluate our results. The previous study assigned plants to 9 kinds of efficacy whereas we assigned the plants to 18 disease classes (16 from NCBI and 2 additional classes). For the sake of evaluation we got done a mapping of the 18 disease classes to 9 efficacy classes by a professional doctor, which is shown in Table 5. Table 6 shows the prediction result of plant-disease relations for all 3 datasets, corresponding to clusters with matching score greater than 0.6. Table 6 also shows corresponding efficacy, the number of assigned plants, number of correctly predicted plants, and true positive rates (TPR), respectively.Table 5
Relation between disease classes in NCBI and efficacy classes reported by Afendi et al. [6].
Class of disease
Ref.
Efficacy class
D1 Blood and lymph diseases
NCBI
E7 Pain/inflammation (PIN)
D2 Cancers
NCBI
E7 Pain/inflammation (PIN)
D3 The digestive system
NCBI
E4 Gastrointestinal disorders (GST)
E7 Pain/inflammation (PIN)
D4 Ear, nose, and throat
NCBI
E7 Pain/inflammation (PIN)
D5 Diseases of the eye
NCBI
E7 Pain/inflammation (PIN)
D6 Female-specific diseases
NCBI
E5 Female reproductive organ problems (FML)
D7 Glands and hormones
NCBI
E7 Pain/inflammation (PIN)
D8 The heart and blood vessels
NCBI
E7 Pain/inflammation (PIN)
D9 Diseases of the immune system
NCBI
E7 Pain/inflammation (PIN)
D10 Male-specific diseases
NCBI
E6 Musculoskeletal and connective tissue disorders (MSC)
D11 Muscle and bone
NCBI
E6 Musculoskeletal and connective tissue disorders (MSC)
D12 Neonatal diseases
NCBI
E7
Pain/inflammation (PIN)
D13 The nervous system
NCBI
E7 Pain/inflammation (PIN)
D14 Nutritional and metabolic diseases
NCBI
E2 Disorders of appetite (DOA)
E4 Gastrointestinal disorders (GST)
D15 Respiratory diseases
NCBI
E8 Respiratory disease (RSP)
E7 Pain/inflammation (PIN)
D16 Skin and connective tissue
NCBI
E9 Wounds and skin infections (WND)
D17 The urinary system
*
E1 Urinary related problems (URI)
D18 Mental and behavioural disorders
*
E3 Disorders of mood and behavior (DMB)Table 6
The prediction result of plant-disease relations using matching score >0.6.
Class of disease
Corresponding efficacy
0.7% dataset
0.5% dataset
0.3% dataset
Number of assigned plants
Correct prediction
True positive rate
Number of assigned plants
Correct prediction
True positive rate
Number of assigned plants
Correct prediction
True positive rate
D1
E7
26
22
0.85
24
20
0.83
24
20
0.83
D2
E7
1
1
1.00
5
5
1.00
1
1
1.00
D3
E4
42
42
1.00
33
33
1.00
28
28
1.00
E7
38
0.90
30
0.91
25
0.89
D4
E7
0
0
—
0
0
—
0
0
—
D5
E7
0
0
—
0
0
—
0
0
—
D6
E5
38
38
1.00
37
37
1.00
32
32
1.00
D7
E7
0
0
—
0
0
—
0
0
—
D8
E7
10
8
0.80
8
7
0.88
6
5
0.83
D9
E7
0
0
—
0
0
—
1
1
1.00
D10
E6
6
4
0.67
2
0
—
3
1
0.33
D11
E6
65
65
1.00
71
71
1.00
60
60
1.00
D12
E7
0
0
—
0
0
—
0
0
—
D13
E7
0
0
—
0
0
—
5
5
1.00
D14
E2
54
44
0.81
45
36
0.80
35
26
0.74
E4
54
1.00
45
1.00
35
1.00
D15
E7
38
37
0.97
34
34
1.00
33
33
1.00
E8
31
0.82
30
0.88
29
0.88
D16
E9
32
31
0.97
32
32
1.00
27
27
1.00
D17
E1
13
13
1.00
9
9
1.00
8
8
1.00
D18
E3
0
0
—
5
5
1.00
4
4
1.00
Total assigned plants
135
129
117We determined TPR corresponding to a disease/efficacy class by calculating the ratio of the number of correct prediction to the number of all predictions. When a disease corresponds to more than one kind of efficacy, the highest TPR can be considered the TPR for the corresponding disease. For all 3 datasets the TPR corresponding to each disease is roughly 90% or more. The 0.3% dataset consists of Jamu pairs with higher correlation values and based on this dataset 117 plants are assigned to 14 disease classes. The 0.7% dataset contains more Jamu pairs and assigned plants to 11 disease classes, one less disease class compared to 0.5% dataset. The two disease classes covered by 0.3% dataset but not covered by 0.5% and 0.7% datasets are the nervous system (D13) and disease of the immune system (D9). The only disease class covered by 0.3% and 0.5% datasets but not covered by 0.7% dataset is mental and behavioural disorders (D18). The larger dataset network tends to have lower coverage of disease classes. The number of Jamu pairs, that is, the number of edges in the network, affect the number of DPClusO resulting clusters and number of Jamu formulas per cluster. As a consequence, for the larger dataset networks, the success rate becomes lower and the coverage of disease classes is lower but prediction of more plant-disease relations can be achieved.


## 3.1. Construction and Comparison of Jamu and Random Networks

We used the same number of Jamu formulas from previous research [6], 3138 Jamu formulas, and the set union of all formulas consists of 465 plants. We assigned 3138 Jamu formulas to 116 diseases of International Classification of Diseases (ICD) version 10 from World Health Organization (WHO, Table 1) [19]. Those 116 diseases are mapped to 18 classes of disease, which contains 16 classes of disease from National Center for Biotechnology Information (NCBI) [20] and 2 additional classes. Table 2 shows distribution of 3138 Jamu into 18 classes of disease. According to this classification, most Jamu formulas are useful for relieving muscle and bone, nutritional and metabolic diseases, and the digestive system. Furthermore, there is no Jamu formula classified into glands and hormones and neonatal disease classes. We excluded 4 Jamu formulas which are used to treat fever in the evaluation process because this symptom is very general and almost appeared in all disease classes. Jamu-plant-disease relations can be represented using 2 matrices: first matrix is Jamu-plant relation with dimension 3138
×
465 and the second matrix is Jamu-disease relation with dimension 3138
×
18.Table 1
List of diseases using International Classification of Diseases ver. 10 (class of disease IDs correspond to Table2).
ID
Disease
Class of disease
1
Abdominal pain
3
2
Abdominal pain, diarrhea
3
3
Acne
16
4
Acne, skin problems (cosmetics)
16
5
Amenorrhoea, dysmenorrhea
6
6
Amenorrhoea, irregular menstruation
6
7
Anaemia
1
8
Appendicitis, urinary tract infection, tonsillitis
3
9
Arthralgia
11
10
Arthralgia, arthritis
11
11
Asthma
15
12
Benign prostatic hyperplasia (Bph)
10
13
Breast disorder
6
14
Bromhidrosis
16
15
Bronchitis
15
16
Cancer
2
17
Cancer pain
2
18
Cancer, inflammation
2
19
Colic abdomen, bloating (in infant)
3
20
Common cold
15
21
Common cold, dyspepsia, insect bites
15, 3, 16
22
Common cold, influenza
15
23
Cough
15
24
Degenerative disease
14
25
Dermatitis, urticaria, erythema
16
26
Diabetes
14
27
Diabetic gangrene
16
28
Diarrhea
3
29
Diarrhea, abdominal pain
3
30
Diseases of the eye
5
31
Disorders in pregnancy
6
32
Dysmenorrhea
6
33
Dysmenorrhea, irregular menstruation
6
34
Dysmenorrhea, menstrual syndrome
6
35
Dyspepsia
3
36
Dyspnoea
15
37
Dyspnoea, cough, orthopnoea
15
38
Fatigue
11
39
Fatigue, anaemia, loss appetite
1
40
Fatigue, lack of sexual function
6
41
Fatigue, low back pain
11
42
Fatigue, myalgia, arthralgia
11
43
Fatigue, osteoarthritis
11
44
Fertility problem
6, 10
45
Fever
0
46
Gastritis, gastric ulcer
3
47
Haemorrhoids
1
48
Headache
13
49
Heart diseases
8
50
Heartburn
3, 8
51
Hepatitis, other diseases of liver
3
52
Hypercholesterolaemia
14
53
Hypertension
8
54
Hypertension, diabetes
14
55
Hypertension, hypercholesterolaemia
14
56
Hyperuricemia
1
57
Immunodefficiency
9
58
Indigestion (K.30)
3
59
Indigestion, lose appetite
3
60
Infertility
6, 10
61
Irregular menstruation, menstruation syndrome
6
62
Kidney diseases
17
63
Lactation problems
6
64
Leukorrhoea (Vaginalis)
6
65
Leukorrhoea (Vaginalis), dysmenorrhoea
6
66
Lose appetite
3
67
Lose appetite, underweight
14
68
Low back pain, myalgia, arthralgia
11
69
Low back pain, myalgia, constipation
11
70
Low back pain, urinary tract infection
17
71
Lung diseases
15
72
Malaise and Fatigue
11
73
Malaise and Fatigue, Constipation
11
74
Malaise and Fatigue, Fertility Problems
10, 11
75
Malaise and Fatigue, Low Back Pain
11
76
Malaise and Fatigue, Sexual Dysfunction
11, 6, 10
77
Malaise and Fatigue, Skin Problems (Cosmetics)
16
78
Malaria, anaemia
1
79
Meno-metrorrhagia
6
80
Menopausal syndrome
6
81
Menopause/menstrual syndrome, leukorrhoea (vaginalis)
6
82
Menstrual syndrome
6
83
Menstrual syndrome, fatigue
6
84
Migraine
13
85
Mood disorder
18
86
Myalgia, arthralgia
11
87
Nausea/vomiting of pregnancy
6
88
Osteoarthritis
11
89
Osteoarthritis, fatigue
11
90
Overweight, obesity
14
91
Paralysis
13
92
Post partum syndrome
6
93
Prevent from overweight
14
94
Respiratory infection due to smoking
15
95
Respiratory tract infection
15
96
Rheumatoid arthritis, gout
11
97
Secondary amenorrhea
6
98
Secondary amenorrhea, irregular menstruation
6
99
Sexual dysfunction, fatigue
6, 10
100
Skin diseases
16
101
Skin problems (cosmetics)
16
102
Sleeping and Mood Disorders
18
103
Sleeping disorders
18
104
Stomatitis
3
105
Stomatitis, gingivitis, tonsilitis
3
106
Stone in kidney (N20.0)
17
107
Stone in kidney (N20.0), urinary bladder stone (N21.0)
17
108
Tonsilitis
4
109
Tonsilofaringitis
4
110
Toothache
13
111
Typhoid, dyspepsia
3
112
Ulcer of anus and rectum
3
113
Underweight, lose appetite
3
114
Urinary tract infection (urethritis)
17
115
Vaginal discharges
6
116
Vaginal diseases
6Table 2
Distribution of Jamu formulas according to 18 classes of disease (classes of diseases are determined by NCBI in ID1 to ID16 and by the present study in ID17 and ID18 represented by asterisks in Ref. columns).
ID
Class of disease (NCBI)
Ref.
Number of Jamu
Percentage
1
Blood and lymph diseases
NCBI
201
6.41
2
Cancers
NCBI
32
1.02
3
The digestive system
NCBI
457
14.56
4
Ear, nose, and throat
NCBI
2
0.06
5
Diseases of the eye
NCBI
1
0.03
6
Female-specific diseases
NCBI
382
12.17
7
Glands and hormones
NCBI
0
—
8
The heart and blood vessels
NCBI
57
1.82
9
Diseases of the immune system
NCBI
22
0.70
10
Male-specific diseases
NCBI
17
0.54
11
Muscle and bone
NCBI
649
20.68
12
Neonatal diseases
NCBI
0
—
13
The nervous system
NCBI
32
1.02
14
Nutritional and metabolic diseases
NCBI
576
18.36
15
Respiratory diseases
NCBI
313
9.97
16
Skin and connective tissue
NCBI
163
5.19
17
The urinary system
*
90
2.87
18
Mental and behavioral disorders
*
21
0.67
The number of Jamu classified into multiple disease classes
119
3.79
The number of Jamu unclassified
4
0.13
Total Jamu formulas
3138
100.00After completion of data acquisition process, we calculated the similarity between Jamu pairs using correlation measure. The similarity measures between Jamu pairs were determined based on their ingredients. Corresponding toK (3138 in present case) Jamu formulas, there can be maximum (
K
×
(
K
-
1
)
/
2
) = (
3138
×
(
3137
/
2
)
) = 4,921,953 Jamu pairs. We sorted the Jamu pairs based on correlation value using descending order and selected top-n (0.7%, 0.5%, and 0.3%) pairs of Jamu formula to create 3 sets of Jamu pairs. The number of Jamu pairs for 0.7%, 0.5%, and 0.3% datasets is 34,454 pairs, 24,610 pairs, and 14,766 pairs and the corresponding minimum correlation values are 0.596, 0.665, and 0.718, respectively. The three datasets of Jamu pairs can be regarded as three undirected networks (step 1 in Figure 1) consisting of 2779, 2496, and 2085 Jamu formulas, respectively (Table 3). Figure 2 shows visualization of 0.7% Jamu networks using Cytoscape Spring Embedded layout. We verified that the degree distributions of the Jamu networks are somehow close to those of scale-free networks, that is, roughly are of power law type. However, in the high-degree region the power law structure is broken (Figure 3). Nearly accurate relation of power laws between medicinal herbs and the number of formulas utilizing them was observed in Jamu system but not in Kampo (Japanese crude drug system) [4]. The difference of formulas between Jamu and Kampo can be explained by herb selection by medicinal researchers based on the optimization process of selection [4]. Thus, the broken structure of power law corresponding to Jamu networks is associated with the fact that selection of Jamu pairs based on ingredient correlation leads to nonrandom selection. We also constructed random networks according to Erdős-Rényi (ER) model [21], Barabási-Albert (BA) model [22], and Vazquez’s Connecting Nearest Neighbor (CNN) model [23] of the same size corresponding to each of the real Jamu network. We used Cytoscape Network Analyzer plugin [24] and R software for analyzing the characteristics of both the Jamu and the random networks.Table 3
Statistics of three datasets.
Parameters
0.7%
0.5%
0.3%
Network statistics
Total pairs
34,454
24,610
14,766
Minimum correlation
0.596
0.665
0.718
Number of Jamu formulas
2,779
2,496
2,085
Average degree
24.8
19.7
14.2
(Random network: ER)
(
24.8
±
0.0
)
(
19.7
±
0.0
)
(
14.2
±
0.0
)
(Random network: BA)
(
24.7
±
0.1
)
(
19.7
±
0.1
)
(
14.1
±
0.1
)
(Random network: CNN)
(
24.7
±
0.4
)
(
19.7
±
0.4
)
(
14.0
±
0.4
)
Clustering coefficient
0.521
0.520
0.540
(Random network: ER)
(
0.009
±
0.000
)
(
0.008
±
0.000
)
(
0.007
±
0.000
)
(Random network: BA)
(
0.030
±
0.001
)
(
0.028
±
0.001
)
(
0.026
±
0.001
)
(Random network: CNN)
(
0.246
±
0.008
)
(
0.239
±
0.008
)
(
0.233
±
0.010
)
Number of connected components
69
119
254
(Random networks: ER, BA, CNN)
(1)
(1)
(1)
Network diameter
15
17
20
(Random network: ER)
(
4.0
±
0.0
)
(
4.0
±
0.0
)
(
5.0
±
0.0
)
(Random network: BA)
(
10.8
±
0.8
)
(
11.2
±
1.5
)
(
10.8
±
0.9
)
(Random network: CNN)
(
14.6
±
1.9
)
(
14.1
±
1.4
)
(
14.7
±
1.3
)
Network density
0.008
0.008
0.007
(Random network: ER)
(
0.009
±
0.000
)
(
0.008
±
0.000
)
(
0.007
±
0.000
)
(Random network: BA)
(
0.009
±
0.000
)
(
0.008
±
0.000
)
(
0.007
±
0.000
)
(Random network: CNN)
(
0.009
±
0.000
)
(
0.008
±
0.000
)
(
0.007
±
0.000
)
DPClusO
Total number of clusters
1,746
1,411
938
Number of clusters with more than 2 Jamu
1,296
873
453
(%)
(74.2)
(61.9)
(48.3)
Number of Jamu formulas in the biggest cluster
118
104
89Figure 2
The network consisting of 0.7% Jamu pairs (correlation value above or equal to 0.596).Figure 3
Degree distributions of three Jamu networks roughly follow power law. Thex-axis corresponds to the log of degree of a node in the Jamu network and the y-axis corresponds to the log of the number of Jamu.We determined five statistical indexes, that is, average degree, clustering coefficient, number of connected component, network diameter, and network density of each Jamu network and also of each random network. The clustering coefficientC
n of a node n is defined as C
n
=
2
e
n
/
(
k
n
(
k
n
-
1
)
), where k
n is the number of neighbors of n and e
n is the number of connected pairs between all neighbors of n. The network diameter is the largest distance between any two nodes. If a network is disconnected, its diameter is the maximum of all diameters of its connected components. A network’s density is the ratio of the number of edges in the network over the total number of possible edges between all pairs of nodes (which is n
(
n
-
1
)
/
2, where n is the number of vertices, for an undirected graph). The average number of neighbors and the network density are the same for the real and random networks of the same size as it is shown in Table 3. In case of 0.7% and 0.5% real networks, the clustering coefficient is roughly the same and in case of 0.3% the clustering coefficient is somewhat larger. The number of connected components and the diameter of the Jamu networks gradually decrease as the network grows bigger by addition of more nodes and edges.Very different values corresponding to clustering coefficient, connected component, and network diameter imply that the Jamu networks are quite different from all 3 types of random networks. The differences between Jamu networks and ER random networks are the largest. Random networks constructed based on other two models are also substantially different from Jamu networks. Based on the fact that the random networks constructed based on all three types of models are different from the Jamu networks, it can be concluded that structure of Jamu networks is reasonably biased and thus might contain certain information about plant-disease relations. Specially, much higher value corresponding to clustering coefficient indicates that there are clusters in the networks worthy to be investigated. To extract clusters from the Jamu networks (step 2 in Figure1) we applied DPClusO network clustering algorithm [14] to generate overlapping clusters based on density and periphery tracking.


## 3.2. Supervised Clustering Based on DPClusO

DPClusO is a general-purpose clustering algorithm and useful for finding overlapping cohesive groups in an undirected simple graph for any type of application. It ensures coverage and performs robustly in case of random addition, removal, and rearrangement of edges in protein-protein interaction (PPI) networks [14]. While applying DPClusO, the parameter values of density and cluster property that we used in this experiment are 0.9 and 0.5, respectively [15]. Table 3 shows the summary of clustering result by DPClusO. Because clusters consisting of two Jamu formulas are trivial clusters, for the next steps we only use clusters each of which consists of 3 or more Jamu formulas. The number of total clusters increases along with the larger dataset, although the threshold correlation between Jamu pairs decreases. We evaluated the clustering result using matching score to determine dominant disease for every cluster (step 3 in Figure 1). Matching score of a cluster is the ratio of the highest number of Jamu associated with the same disease to the total number of Jamu in the cluster. Thus matching score is a measure to indicate how strongly a disease is associated to a cluster. Figure 4 shows the distribution of the clusters with respect to matching score from three datasets. All datasets have the highest frequency of clusters at matching score >0.9 and overall most of the clusters have higher matching score, which means most of the DPClusO generated clusters can be confidently related to a dominant disease. Furthermore the number of clusters with matching score >0.9 is remarkably larger compared to the same in other ranges of matching score in case of the 0.3% dataset (Figure 4(c)). If we compare the ratio of frequency of clusters at matching score >0.9 for every dataset, the 0.3% dataset has the highest ratio with 40.84% (of 453), compared to 29.67% (of 873) and 21.91% (of 1296), in case of 0.5% and 0.7% datasets, respectively. Thus, the most reliable species to disease relations can be predicted at matching score >0.9 corresponding to the clusters generated from 0.3% dataset.Distribution of clusters based on matching score.
(a)
0.7%
(b)
0.5%
(c)
0.3%Figure5(a) shows the success rate for all 3 datasets with respect to threshold matching scores. Success rate is defined as the ratio of the number of clusters with matching score larger than the threshold to the total number of clusters. As expected it tends to produce lower success rate if we decrease correlation value to create the datasets. However more clusters are generated and more information can be extracted when we lower the threshold correlation value. The success rate increases rapidly as the matching score decreases from 0.9 to 0.6 and after that the slope of increase of success rate decreases. Therefore in this study we empirically decide 0.6 as the threshold matching score to predict plant-disease relations.(a) Success rate and (b) number of predicted plants with respect to matching score thresholds.
(a)
(b)


## 3.3. Assignment of Plants to Disease

By using DPClusO resulting clusters, we assigned plants to classes of disease. Based on a threshold matching score we assigned dominant disease to a cluster. Then we assign a plant to a cluster by way of analyzing the ingredients of the Jamu formulas belonging to that cluster and determining the highest frequency plant, that is, the plant that is used for maximum number Jamu belonging to that cluster (step 4 in Figure1). Thus we assign a disease and a plant to each cluster having matching score greater than a threshold. Our hypothesis is that the disease and the plant assigned to the same cluster are related.The total number of assigned plants depends on matching score value. Figure5(b) shows the number of predicted plants that can be assigned to diseases in the context of matching score. With higher matching score value, the number of predicted plants assigned to classes of disease is supposed to remain similar or decrease but the reliability of prediction increases. In Figure 5(b) a sudden change in the number of predicted plants is seen at matching score 0.6 which we consider as empirical threshold in this work. Based on the 0.7% dataset, the largest number of plants (135 plants, Table 4) was assigned to diseases. There are 63 plants assigned to only one class of disease, whereas the other 72 plants are assigned to at least two or more classes of disease (Figure 6).Table 4
List of plants assigned to each disease.
Number
Plants  name
Hit-miss  status
A.  Disease:  blood  and  lymph diseases
1
Tamarindus  indica
Hit
*
2
Allium  sativum
Hit
*
3
Tinospora  tuberculata
Hit
*
4
Piper  retrofractum
Hit
5
Syzygium  aromaticum
Hit
*
6
Bupleurum  falcatum
Hit
7
Graptophyllum  pictum
Hit
8
Plantago  major
Hit
9
Zingiber  officinale
Hit
*
10
Cinnamomum
burmannii
Hit
*
11
Soya  max
Miss
*
12
Kaempferia  galanga
Hit
13
Curcuma  longa
Hit
*
14
Piper  nigrum
Hit
15
Zingiber  aromaticum
Hit
*
16
Phyllanthus  urinaria
Hit
*
17
Oryza  sativa
Hit
18
Myristica  fragrans
Hit
*
19
Alstonia  scholaris
Hit
*
20
Syzygium  polyanthum
Miss
21
Andrographis  paniculata
Hit
*
22
Sida  rhombifolia
Miss
23
Cyperus  rotundus
Hit
24
Sonchus  arvensis
Miss
25
Curcuma  aeruginosa
Hit
*
26
Curcuma  xanthorrhiza
Hit
B.  Disease:  cancers
1
Catharanthus  roseus
Hit
C.  Disease:  the  digestive  system
1
Foeniculum  vulgare
Hit
2
Glycyrrhiza  uralensis
Hit
*
3
Imperata  cylindrica
Hit
4
Zingiber  purpureum
Hit
*
5
Physalis  peruviana
Hit
6
Punica  granatum
Hit
*
7
Echinacea  purpurea
Hit
8
Zingiber  officinale
Hit
*
9
Psidium  guajava
Hit
10
Baeckea  frutescens
Hit
*
11
Amomum  compactum
Hit
12
Cinnamomum
burmannii
Hit
*
13
Melaleuca  leucadendra
Hit
14
Caesalpinia  sappan
Hit
*
15
Parkia  roxburghii
Hit
16
Rheum  tanguticum
Hit
17
Kaempferia  galanga
Hit
18
Coriandrum  sativum
Hit
19
Curcuma  longa
Hit
20
Zingiber  aromaticum
Hit
21
Phyllanthus  urinaria
Hit
22
Myristica  fragrans
Hit
23
Hydrocotyle  asiatica
Hit
*
24
Carica  papaya
Hit
25
Mentha  arvensis
Hit
26
Lepiniopsis  ternatensis
Hit
27
Helicteres  isora
Hit
28
Andrographis  paniculata
Hit
29
Symplocos  odoratissima
Hit
30
Schisandra  chinensis
Hit
31
Blumea  balsamifera
Hit
32
Silybum  marianum
Hit
*
33
Cinnamomum
sintoc
Hit
34
Elephantopus  scaber
Hit
35
Curcuma  aeruginosa
Hit
36
Kaempferia  pandurata
Hit
37
Curcuma  xanthorrhiza
Hit
38
Curcuma  mangga
Hit
*
39
Curcuma  zedoaria
Hit
40
Daucus  carota
Hit
*
41
Matricaria  chamomilla
Hit
*
42
Cymbopogon  nardus
Hit
*
D.  Disease:  female-specific  diseases
1
Foeniculum  vulgare
Hit
2
Imperata  cylindrica
Hit
3
Tamarindus  indica
Hit
4
Pluchea  indica
Hit
*
5
Piper  retrofractum
Hit
6
Punica  granatum
Hit
7
Uncaria  rhynchophylla
Hit
8
Zingiber  officinale
Hit
9
Guazuma  ulmifolia
Hit
*
10
Nigella  sativa
Hit
11
Terminalia  bellirica
Hit
12
Baeckea  frutescens
Hit
13
Phaseolus  radiatus
Hit
14
Amomum  compactum
Hit
*
15
Sauropus  androgynus
Hit
16
Usnea  misaminensis
Hit
17
Cinnamomum
burmannii
Hit
18
Melaleuca  leucadendra
Hit
19
Parameria  laevigata
Hit
20
Parkia  roxburghii
Hit
21
Piper  cubeba
Hit
22
Kaempferia  galanga
Hit
23
Coriandrum  sativum
Hit
24
Kaempferia  angustifolia
Hit
25
Curcuma  longa
Hit
26
Zingiber  aromaticum
Hit
27
Languas  galanga
Hit
28
Galla  lusitania
Hit
29
Quercus  lusitanica
Hit
30
Hydrocotyle  asiatica
Hit
31
Areca  catechu
Hit
32
Lepiniopsis  ternatensis
Hit
33
Helicteres  isora
Hit
*
34
Piper  betle
Hit
35
Elephantopus  scaber
Hit
*
36
Kaempferia  pandurata
Hit
37
Curcuma  xanthorrhiza
Hit
38
Sesbania  grandiflora
Hit
E.  Disease:  the  heart  and  blood  vessels
1
Allium  sativum
Hit
2
Curcuma  longa
Hit
*
3
Morinda  citrifolia
Hit
*
4
Homalomena  occulta
Hit
*
5
Hydrocotyle  asiatica
Hit
6
Alstonia  scholaris
Hit
*
7
Syzygium  polyanthum
Miss
*
8
Andrographis  paniculata
Hit
*
9
Apium  graveolens
Miss
10
Imperata  cylindrica
Hit
F.  Disease:  male-specific  diseases
1
Cucurbita  pepo
Miss
2
Serenoa  repens
Miss
3
Baeckea  frutescens
Hit
4
Phaseolus  radiatus
Hit
5
Curcuma  longa
Hit
6
Elephantopus  scaber
Hit
G.  Disease:  muscle  and  bone
1
Foeniculum  vulgare
Hit
2
Clausena  anisum-olens
Hit
*
3
Zingiber  purpureum
Hit
4
Allium  sativum
Hit
5
Strychnos  ligustrina
Hit
6
Tinospora  tuberculata
Hit
*
7
Piper  retrofractum
Hit
8
Syzygium  aromaticum
Hit
9
Cola  nitida
Hit
*
10
Ginkgo  biloba
Hit
*
11
Panax  ginseng
Hit
12
Equisetum  debile
Hit
*
13
Zingiber  officinale
Hit
14
Ganoderma  lucidum
Hit
15
Nigella  sativa
Hit
16
Terminalia  bellirica
Hit
*
17
Baeckea  frutescens
Hit
*
18
Amomum  compactum
Hit
19
Cinnamomum
burmannii
Hit
20
Melaleuca  leucadendra
Hit
21
Parameria  laevigata
Hit
*
22
Psophocarpus  tetragonolobus
Hit
*
23
Parkia  roxburghii
Hit
24
Piper  cubeba
Hit
*
25
Kaempferia  galanga
Hit
26
Coriandrum  sativum
Hit
27
Cola  acuminata
Hit
28
Coffea  arabica
Hit
29
Orthosiphon  stamineus
Hit
30
Curcuma  longa
Hit
31
Piper  nigrum
Hit
32
Alpinia  galanga
Hit
33
Vitex  trifolia
Hit
34
Zingiber  amaricans
Hit
*
35
Zingiber  zerumbet
Hit
36
Zingiber  aromaticum
Hit
37
Languas  galanga
Hit
38
Massoia  aromatica
Hit
39
Morinda  citrifolia
Hit
40
Carum  copticum
Hit
*
41
Panax  pseudoginseng
Hit
*
42
Oryza  sativa
Hit
43
Myristica  fragrans
Hit
44
Pandanus  amaryllifolius
Hit
45
Eurycoma  longifolia
Hit
46
Hydrocotyle  asiatica
Hit
47
Areca  catechu
Hit
*
48
Mentha  arvensis
Hit
*
49
Lepiniopsis  ternatensis
Hit
50
Pimpinella  pruatjan
Hit
51
Andrographis  paniculata
Hit
52
Blumea  balsamifera
Hit
53
Cymbopogon  nardus
Hit
54
Sida  rhombifolia
Hit
55
Cinnamomum
sintoc
Hit
56
Piper  betle
Hit
*
57
Talinum  paniculatum
Hit
58
Elephantopus  scaber
Hit
59
Cyperus  rotundus
Hit
60
Curcuma  aeruginosa
Hit
61
Kaempferia  pandurata
Hit
*
62
Curcuma  xanthorrhiza
Hit
63
Tribulus  terrestris
Hit
64
Corydalis  yanhusuo
Hit
65
Pausinystalia  yohimbe
Hit
H.  Disease:  nutritional  and metabolic  diseases
1
Foeniculum  vulgare
Hit
2
Glycyrrhiza  uralensis
Hit
3
Zingiber  purpureum
Hit
4
Allium  sativum
Hit
5
Tinospora  tuberculata
Hit
6
Pandanus  conoideus
Hit
7
Syzygium  aromaticum
Hit
8
Punica  granatum
Hit
9
Zingiber  officinale
Hit
10
Guazuma  ulmifolia
Hit
11
Nigella  sativa
Hit
12
Amomum  compactum
Hit
*
13
Cinnamomum
burmannii
Hit
14
Parameria  laevigata
Hit
15
Caesalpinia  sappan
Hit
16
Soya  max
Hit
*
17
Cocos  nucifera
Hit
18
Rheum  tanguticum
Hit
19
Piper  cubeba
Hit
*
20
Murraya  paniculata
Hit
21
Kaempferia  galanga
Hit
*
22
Coffea  arabica
Hit
*
23
Orthosiphon  stamineus
Hit
24
Curcuma  longa
Hit
25
Piper  nigrum
Hit
*
26
Zingiber  aromaticum
Hit
27
Aloe  vera
Hit
28
Phaleria  papuana
Hit
29
Galla  lusitania
Hit
30
Quercus  lusitanica
Hit
31
Morinda  citrifolia
Hit
32
Myristica  fragrans
Hit
*
33
Momordica  charantia
Hit
34
Areca  catechu
Hit
35
Lepiniopsis  ternatensis
Hit
36
Alstonia  scholaris
Hit
37
Hibiscus  sabdariffa
Hit
38
Laminaria  japonica
Hit
39
Syzygium  polyanthum
Hit
40
Andrographis  paniculata
Hit
41
Sindora  sumatrana
Hit
*
42
Cassia  angustifolia
Hit
43
Woodfordia  floribunda
Hit
44
Piper  betle
Hit
45
Spirulina
Hit
46
Stevia  rebaudiana
Hit
47
Theae  sinensis
Hit
48
Sonchus  arvensis
Hit
49
Curcuma  heyneana
Hit
50
Curcuma  aeruginosa
Hit
51
Kaempferia  pandurata
Hit
*
52
Curcuma  xanthorrhiza
Hit
53
Curcuma  zedoaria
Hit
*
54
Olea  europaea
Hit
I.  Disease  respiratory  diseases
1
Foeniculum  vulgare
Hit
2
Clausena  anisum-olens
Hit
3
Glycyrrhiza  uralensis
Hit
4
Zingiber  purpureum
Hit
5
Piper  retrofractum
Hit
*
6
Syzygium  aromaticum
Hit
7
Gaultheria  punctata
Hit
8
Panax  ginseng
Hit
9
Equisetum  debile
Hit
*
10
Zingiber  officinale
Hit
11
Citrus  aurantium
Hit
*
12
Nigella  sativa
Hit
*
13
Amomum  compactum
Hit
14
Cinnamomum
burmannii
Hit
15
Melaleuca  leucadendra
Hit
16
Parkia  roxburghii
Hit
17
Cocos  nucifera
Hit
18
Piper  cubeba
Hit
19
Kaempferia  galanga
Hit
20
Coriandrum  sativum
Hit
21
Curcuma  longa
Hit
22
Piper  nigrum
Hit
23
Zingiber  aromaticum
Hit
24
Languas  galanga
Hit
25
Mentha  piperita
Hit
26
Oryza  sativa
Hit
*
27
Myristica  fragrans
Hit
28
Pandanus  amaryllifolius
Hit
*
29
Hydrocotyle  asiatica
Hit
*
30
Mentha  arvensis
Hit
31
Lepiniopsis  ternatensis
Hit
32
Helicteres  isora
Hit
33
Blumea  balsamifera
Hit
34
Cymbopogon  nardus
Hit
35
Piper  betle
Hit
36
Curcuma  xanthorrhiza
Hit
37
Salix  alba
Hit
*
38
Matricaria  chamomilla
Miss
*
J.  Disease:  skin  and  connective  tissue
1
Strychnos  ligustrina
Hit
2
Merremia  mammosa
Hit
*
3
Piper  retrofractum
Hit
*
4
Santalum  album
Hit
5
Zingiber  officinale
Hit
*
6
Citrus  aurantium
Hit
7
Citrus  hystrix
Hit
8
Cassia  siamea
Hit
9
Cocos  nucifera
Hit
10
Trigonella  foenum-graecum
Hit
11
Orthosiphon  stamineus
Hit
12
Curcuma  longa
Hit
13
Vetiveria  zizanioides
Hit
14
Aloe  vera
Hit
15
Rosa  chinensis
Hit
16
Jasminum  sambac
Hit
17
Phyllanthus  urinaria
Hit
18
Mentha  piperita
Hit
19
Oryza  sativa
Hit
20
Myristica  fragrans
Hit
*
21
Hydrocotyle  asiatica
Hit
22
Lepiniopsis  ternatensis
Hit
23
Alstonia  scholaris
Hit
24
Andrographis  paniculata
Hit
25
Cymbopogon  nardus
Hit
26
Piper  betle
Hit
27
Theae  sinensis
Hit
28
Curcuma  heyneana
Hit
29
Kaempferia  pandurata
Hit
*
30
Curcuma  xanthorrhiza
Hit
31
Melaleuca  leucadendra
Hit
32
Matricaria  chamomilla
Miss
*
K.  Disease:  the  urinary  system
1
Foeniculum  vulgare
Hit
*
2
Imperata  cylindrica
Hit
*
3
Strychnos  ligustrina
Hit
*
4
Plantago  major
Hit
5
Zingiber  officinale
Hit
*
6
Cinnamomum
burmannii
Hit
*
7
Strobilanthes  crispus
Hit
8
Kaempferia  galanga
Hit
*
9
Orthosiphon  stamineus
Hit
10
Phyllanthus  urinaria
Hit
11
Blumea  balsamifera
Hit
*
12
Sonchus  arvensis
Hit
13
Curcuma  xanthorrhiza
Hit
*indicates that plant will not assigned if we use matching score >0.7.Figure 6
Distribution of 135 plants assigned based on 0.7% dataset with respect to the number of diseases they are assigned to.


## 3.4. Evaluation of the Supervised Clustering Based on DPClusO

We used previously published results [6] as gold standard to evaluate our results. The previous study assigned plants to 9 kinds of efficacy whereas we assigned the plants to 18 disease classes (16 from NCBI and 2 additional classes). For the sake of evaluation we got done a mapping of the 18 disease classes to 9 efficacy classes by a professional doctor, which is shown in Table 5. Table 6 shows the prediction result of plant-disease relations for all 3 datasets, corresponding to clusters with matching score greater than 0.6. Table 6 also shows corresponding efficacy, the number of assigned plants, number of correctly predicted plants, and true positive rates (TPR), respectively.Table 5
Relation between disease classes in NCBI and efficacy classes reported by Afendi et al. [6].
Class of disease
Ref.
Efficacy class
D1 Blood and lymph diseases
NCBI
E7 Pain/inflammation (PIN)
D2 Cancers
NCBI
E7 Pain/inflammation (PIN)
D3 The digestive system
NCBI
E4 Gastrointestinal disorders (GST)
E7 Pain/inflammation (PIN)
D4 Ear, nose, and throat
NCBI
E7 Pain/inflammation (PIN)
D5 Diseases of the eye
NCBI
E7 Pain/inflammation (PIN)
D6 Female-specific diseases
NCBI
E5 Female reproductive organ problems (FML)
D7 Glands and hormones
NCBI
E7 Pain/inflammation (PIN)
D8 The heart and blood vessels
NCBI
E7 Pain/inflammation (PIN)
D9 Diseases of the immune system
NCBI
E7 Pain/inflammation (PIN)
D10 Male-specific diseases
NCBI
E6 Musculoskeletal and connective tissue disorders (MSC)
D11 Muscle and bone
NCBI
E6 Musculoskeletal and connective tissue disorders (MSC)
D12 Neonatal diseases
NCBI
E7
Pain/inflammation (PIN)
D13 The nervous system
NCBI
E7 Pain/inflammation (PIN)
D14 Nutritional and metabolic diseases
NCBI
E2 Disorders of appetite (DOA)
E4 Gastrointestinal disorders (GST)
D15 Respiratory diseases
NCBI
E8 Respiratory disease (RSP)
E7 Pain/inflammation (PIN)
D16 Skin and connective tissue
NCBI
E9 Wounds and skin infections (WND)
D17 The urinary system
*
E1 Urinary related problems (URI)
D18 Mental and behavioural disorders
*
E3 Disorders of mood and behavior (DMB)Table 6
The prediction result of plant-disease relations using matching score >0.6.
Class of disease
Corresponding efficacy
0.7% dataset
0.5% dataset
0.3% dataset
Number of assigned plants
Correct prediction
True positive rate
Number of assigned plants
Correct prediction
True positive rate
Number of assigned plants
Correct prediction
True positive rate
D1
E7
26
22
0.85
24
20
0.83
24
20
0.83
D2
E7
1
1
1.00
5
5
1.00
1
1
1.00
D3
E4
42
42
1.00
33
33
1.00
28
28
1.00
E7
38
0.90
30
0.91
25
0.89
D4
E7
0
0
—
0
0
—
0
0
—
D5
E7
0
0
—
0
0
—
0
0
—
D6
E5
38
38
1.00
37
37
1.00
32
32
1.00
D7
E7
0
0
—
0
0
—
0
0
—
D8
E7
10
8
0.80
8
7
0.88
6
5
0.83
D9
E7
0
0
—
0
0
—
1
1
1.00
D10
E6
6
4
0.67
2
0
—
3
1
0.33
D11
E6
65
65
1.00
71
71
1.00
60
60
1.00
D12
E7
0
0
—
0
0
—
0
0
—
D13
E7
0
0
—
0
0
—
5
5
1.00
D14
E2
54
44
0.81
45
36
0.80
35
26
0.74
E4
54
1.00
45
1.00
35
1.00
D15
E7
38
37
0.97
34
34
1.00
33
33
1.00
E8
31
0.82
30
0.88
29
0.88
D16
E9
32
31
0.97
32
32
1.00
27
27
1.00
D17
E1
13
13
1.00
9
9
1.00
8
8
1.00
D18
E3
0
0
—
5
5
1.00
4
4
1.00
Total assigned plants
135
129
117We determined TPR corresponding to a disease/efficacy class by calculating the ratio of the number of correct prediction to the number of all predictions. When a disease corresponds to more than one kind of efficacy, the highest TPR can be considered the TPR for the corresponding disease. For all 3 datasets the TPR corresponding to each disease is roughly 90% or more. The 0.3% dataset consists of Jamu pairs with higher correlation values and based on this dataset 117 plants are assigned to 14 disease classes. The 0.7% dataset contains more Jamu pairs and assigned plants to 11 disease classes, one less disease class compared to 0.5% dataset. The two disease classes covered by 0.3% dataset but not covered by 0.5% and 0.7% datasets are the nervous system (D13) and disease of the immune system (D9). The only disease class covered by 0.3% and 0.5% datasets but not covered by 0.7% dataset is mental and behavioural disorders (D18). The larger dataset network tends to have lower coverage of disease classes. The number of Jamu pairs, that is, the number of edges in the network, affect the number of DPClusO resulting clusters and number of Jamu formulas per cluster. As a consequence, for the larger dataset networks, the success rate becomes lower and the coverage of disease classes is lower but prediction of more plant-disease relations can be achieved.


## 4. Conclusions

This paper introduces a novel method called supervised clustering for analyzing big biological data by integrating network clustering and selection of clusters based on supervised learning. In the present work we applied the method for data mining of Jamu formulas accumulated in KNApSAcK database. Jamu networks were constructed based on correlation similarities between Jamu formulas and then network clustering algorithm DPClusO was applied to generate high density Jamu modules. For the analysis of the next steps potential clusters were selected by supervised learning. The successful clusters containing several Jamu related to the same disease might be useful for finding main ingredient plant for that disease and the lower matching score value clusters will be associated with varying plants which might be supporting ingredients. By applying the proposed method important plants from Jamu formulas for every classes of disease were determined. The plant to disease relations predicted by proposed network based method were evaluated in the context of previously published results and were found to produce a TPR of 90%. For the larger dataset networks, success rate and the coverage of disease classes become lower but prediction of more plant-disease relations can be achieved.



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*Source: 831751-2014-04-07.xml*