Disease Clusters?

Groups of diseases that share a large number of curated genes with each other, computed via label propagation over the shared-gene similarity graph. See also Shared-Gene Disease Pairs for pairwise comparisons.

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Cluster 73

13 diseases · 20 shared-gene connections
13 Diseases
1,218 Unique genes
0.096 Avg. similarity score
Ischemic heart disease Most-connected disease (6 links)
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Disease Pinned (dragged)
Node size = connections within this cluster · edge thickness = similarity strength · hover an edge for its details · click a node to select it and show its pairs below (double-click or Ctrl/⌘-click opens the disease page) · drag a node to pin it in place · scroll/pinch to zoom.

Member diseases (most connected first ‐ the cluster's core)

Disease ⇵ Connections in cluster ⇵ Significant partners ⇵ Curated genes ⇵
Ischemic heart disease 6 6 170
Heart disease 5 5 146
Atherosclerosis 4 4 119
Kidney failure 4 4 251
Myocardial ischemia 4 4 391
Cerebrovascular disorder 3 3 84
Erectile dysfunction 3 3 61
Large artery stroke 3 3 78
Preeclampsia 3 3 98
Kidney disease 2 2 425
Acetyl-coa carboxylase deficiency 1 1 1
Peho-like syndrome 1 1 1
Zaki syndrome 1 1 1

Top shared genes (genes linked to 2+ member diseases ‐ top 100 shown, download for all)

Gene ⇵ Member diseases ⇵ Linked diseases
EDN1 8 / 13 Atherosclerosis, Cerebrovascular disorder, Erectile dysfunction, Ischemic heart disease and 4 more
AGT 7 / 13 Atherosclerosis, Cerebrovascular disorder, Heart disease, Kidney disease and 3 more
MTHFR 7 / 13 Atherosclerosis, Cerebrovascular disorder, Ischemic heart disease, Kidney disease and 3 more
NOS3 7 / 13 Atherosclerosis, Erectile dysfunction, Heart disease, Ischemic heart disease and 3 more
VEGFA 7 / 13 Atherosclerosis, Erectile dysfunction, Heart disease, Ischemic heart disease and 3 more
ACE 6 / 13 Cerebrovascular disorder, Ischemic heart disease, Kidney disease, Kidney failure and 2 more
APOE 6 / 13 Atherosclerosis, Cerebrovascular disorder, Heart disease, Ischemic heart disease and 2 more
ATXN2 6 / 13 Atherosclerosis, Cerebrovascular disorder, Heart disease, Kidney disease and 2 more
CRP 6 / 13 Atherosclerosis, Cerebrovascular disorder, Heart disease, Ischemic heart disease and 2 more
EDNRA 6 / 13 Atherosclerosis, Cerebrovascular disorder, Erectile dysfunction, Heart disease and 2 more
FTO 6 / 13 Heart disease, Ischemic heart disease, Kidney disease, Kidney failure and 2 more
LPA 6 / 13 Atherosclerosis, Cerebrovascular disorder, Heart disease, Kidney disease and 2 more
PTGS2 6 / 13 Atherosclerosis, Cerebrovascular disorder, Ischemic heart disease, Kidney disease and 2 more
ABO 5 / 13 Cerebrovascular disorder, Heart disease, Ischemic heart disease, Large artery stroke and 1 more
ADAMTS7 5 / 13 Heart disease, Ischemic heart disease, Kidney disease, Kidney failure and 1 more
AGTR1 5 / 13 Cerebrovascular disorder, Ischemic heart disease, Kidney disease, Kidney failure and 1 more
APOA1 5 / 13 Atherosclerosis, Cerebrovascular disorder, Ischemic heart disease, Kidney disease and 1 more
CELSR2 5 / 13 Cerebrovascular disorder, Heart disease, Ischemic heart disease, Large artery stroke and 1 more
CYBA 5 / 13 Atherosclerosis, Heart disease, Ischemic heart disease, Kidney failure and 1 more
EPO 5 / 13 Heart disease, Ischemic heart disease, Kidney disease, Kidney failure and 1 more
FURIN 5 / 13 Heart disease, Ischemic heart disease, Large artery stroke, Myocardial ischemia and 1 more
HDAC9 5 / 13 Atherosclerosis, Cerebrovascular disorder, Heart disease, Large artery stroke and 1 more
LDLR 5 / 13 Atherosclerosis, Cerebrovascular disorder, Heart disease, Ischemic heart disease and 1 more
PHACTR1 5 / 13 Atherosclerosis, Heart disease, Ischemic heart disease, Large artery stroke and 1 more
PLG 5 / 13 Heart disease, Kidney disease, Kidney failure, Large artery stroke and 1 more
PSRC1 5 / 13 Cerebrovascular disorder, Heart disease, Ischemic heart disease, Large artery stroke and 1 more
SERPINE1 5 / 13 Atherosclerosis, Ischemic heart disease, Kidney failure, Myocardial ischemia and 1 more
SMARCA4 5 / 13 Atherosclerosis, Cerebrovascular disorder, Heart disease, Large artery stroke and 1 more
TDRD15 5 / 13 Atherosclerosis, Erectile dysfunction, Heart disease, Myocardial ischemia and 1 more
TGFB1 5 / 13 Cerebrovascular disorder, Heart disease, Kidney disease, Kidney failure and 1 more
TNF 5 / 13 Atherosclerosis, Cerebrovascular disorder, Ischemic heart disease, Kidney failure and 1 more
TWIST1 5 / 13 Atherosclerosis, Cerebrovascular disorder, Ischemic heart disease, Large artery stroke and 1 more
ZC3HC1 5 / 13 Erectile dysfunction, Heart disease, Ischemic heart disease, Large artery stroke and 1 more
ABCA1 4 / 13 Atherosclerosis, Ischemic heart disease, Kidney failure, Myocardial ischemia
ABCG8 4 / 13 Heart disease, Ischemic heart disease, Large artery stroke, Myocardial ischemia
ADIPOQ 4 / 13 Atherosclerosis, Ischemic heart disease, Kidney failure, Myocardial ischemia
AGER 4 / 13 Atherosclerosis, Ischemic heart disease, Kidney failure, Myocardial ischemia
ALB 4 / 13 Cerebrovascular disorder, Heart disease, Kidney disease, Kidney failure
ALOX5AP 4 / 13 Atherosclerosis, Ischemic heart disease, Kidney disease, Myocardial ischemia
CCL2 4 / 13 Atherosclerosis, Ischemic heart disease, Kidney failure, Myocardial ischemia
F2 4 / 13 Cerebrovascular disorder, Heart disease, Ischemic heart disease, Myocardial ischemia
GSTM1 4 / 13 Atherosclerosis, Ischemic heart disease, Kidney failure, Myocardial ischemia
HECTD4 4 / 13 Ischemic heart disease, Kidney disease, Kidney failure, Myocardial ischemia
HMOX1 4 / 13 Ischemic heart disease, Kidney failure, Myocardial ischemia, Preeclampsia
IL6 4 / 13 Atherosclerosis, Cerebrovascular disorder, Kidney failure, Myocardial ischemia
JCAD 4 / 13 Heart disease, Ischemic heart disease, Large artery stroke, Myocardial ischemia
KIF6 4 / 13 Ischemic heart disease, Kidney disease, Kidney failure, Myocardial ischemia
LEPR 4 / 13 Ischemic heart disease, Kidney disease, Kidney failure, Myocardial ischemia
LIPA 4 / 13 Heart disease, Ischemic heart disease, Large artery stroke, Myocardial ischemia
MMP1 4 / 13 Atherosclerosis, Ischemic heart disease, Kidney failure, Myocardial ischemia
MMP12 4 / 13 Cerebrovascular disorder, Ischemic heart disease, Large artery stroke, Myocardial ischemia
MMP3 4 / 13 Ischemic heart disease, Kidney failure, Large artery stroke, Myocardial ischemia
NOS2 4 / 13 Atherosclerosis, Cerebrovascular disorder, Kidney disease, Kidney failure
NPPB 4 / 13 Atherosclerosis, Heart disease, Ischemic heart disease, Myocardial ischemia
PLA2G7 4 / 13 Atherosclerosis, Cerebrovascular disorder, Ischemic heart disease, Myocardial ischemia
PLPP3 4 / 13 Heart disease, Ischemic heart disease, Large artery stroke, Myocardial ischemia
PON1 4 / 13 Atherosclerosis, Heart disease, Ischemic heart disease, Myocardial ischemia
PPARA 4 / 13 Ischemic heart disease, Kidney disease, Kidney failure, Myocardial ischemia
SCARB1 4 / 13 Heart disease, Kidney disease, Kidney failure, Myocardial ischemia
SH2B3 4 / 13 Cerebrovascular disorder, Ischemic heart disease, Large artery stroke, Myocardial ischemia
TCF21 4 / 13 Heart disease, Ischemic heart disease, Large artery stroke, Myocardial ischemia
TCF7L2 4 / 13 Atherosclerosis, Kidney disease, Kidney failure, Myocardial ischemia
TLR4 4 / 13 Atherosclerosis, Ischemic heart disease, Kidney failure, Myocardial ischemia
ABCG5 3 / 13 Atherosclerosis, Ischemic heart disease, Myocardial ischemia
ACP1 3 / 13 Ischemic heart disease, Large artery stroke, Myocardial ischemia
AHSG 3 / 13 Ischemic heart disease, Kidney failure, Myocardial ischemia
ANGPTL4 3 / 13 Heart disease, Ischemic heart disease, Myocardial ischemia
ANK2 3 / 13 Cerebrovascular disorder, Heart disease, Preeclampsia
APOB 3 / 13 Atherosclerosis, Ischemic heart disease, Myocardial ischemia
APOC1 3 / 13 Atherosclerosis, Heart disease, Myocardial ischemia
APOC3 3 / 13 Ischemic heart disease, Kidney failure, Myocardial ischemia
ATP2B1 3 / 13 Heart disease, Ischemic heart disease, Myocardial ischemia
B2M 3 / 13 Heart disease, Kidney disease, Kidney failure
CDH13 3 / 13 Erectile dysfunction, Heart disease, Myocardial ischemia
CLCN6 3 / 13 Ischemic heart disease, Myocardial ischemia, Preeclampsia
CLU 3 / 13 Atherosclerosis, Kidney disease, Kidney failure
CNNM2 3 / 13 Kidney disease, Large artery stroke, Myocardial ischemia
COL4A2 3 / 13 Atherosclerosis, Heart disease, Myocardial ischemia
CUBN 3 / 13 Ischemic heart disease, Kidney disease, Myocardial ischemia
DDAH2 3 / 13 Ischemic heart disease, Myocardial ischemia, Preeclampsia
EPHX2 3 / 13 Ischemic heart disease, Kidney failure, Myocardial ischemia
ESR1 3 / 13 Atherosclerosis, Ischemic heart disease, Myocardial ischemia
F5 3 / 13 Cerebrovascular disorder, Heart disease, Kidney failure
FABP2 3 / 13 Ischemic heart disease, Kidney failure, Myocardial ischemia
FCGR2A 3 / 13 Atherosclerosis, Ischemic heart disease, Myocardial ischemia
FGA 3 / 13 Cerebrovascular disorder, Heart disease, Kidney disease
FGB 3 / 13 Ischemic heart disease, Kidney failure, Myocardial ischemia
FGF2 3 / 13 Erectile dysfunction, Kidney disease, Myocardial ischemia
FGF5 3 / 13 Kidney disease, Kidney failure, Preeclampsia
GATM 3 / 13 Kidney disease, Kidney failure, Myocardial ischemia
GPX1 3 / 13 Ischemic heart disease, Kidney failure, Myocardial ischemia
GSTP1 3 / 13 Kidney disease, Kidney failure, Myocardial ischemia
GSTT1 3 / 13 Ischemic heart disease, Kidney failure, Myocardial ischemia
HBB 3 / 13 Heart disease, Kidney disease, Kidney failure
HHIPL1 3 / 13 Heart disease, Ischemic heart disease, Myocardial ischemia
HMGCR 3 / 13 Ischemic heart disease, Kidney failure, Myocardial ischemia
HSPA1A 3 / 13 Atherosclerosis, Kidney failure, Myocardial ischemia
ICA1L 3 / 13 Heart disease, Ischemic heart disease, Myocardial ischemia
ICAM1 3 / 13 Atherosclerosis, Cerebrovascular disorder, Myocardial ischemia
IGF1 3 / 13 Kidney disease, Kidney failure, Myocardial ischemia
What do these columns mean?
Connections in cluster
How many other members this disease has a shared-gene link to (the node size in the network above). The most-connected diseases are the cluster's core.
Significant partners
How many of those links are statistically significant (FDR q < 0.05).
Curated genes
Distinct curated genes linked to that disease in GeDiPNet.
Member diseases (Top shared genes)
How many of this cluster's diseases are linked to the gene, out of the cluster's total. Genes shared by many members are the most direct explanation of why they group together.
Overlap genes (x / y)
x = genes shared between this cluster and the pathway/GO term; y = that pathway/GO term's total gene count. A higher x relative to y (and to the cluster's own size) means a tighter biological match.
Cluster gene count
Total distinct genes across every disease in this cluster -- the "n" used in the significance test below.
Fold enrichment
Observed overlap divided by the overlap expected by chance, given the cluster's gene count, the pathway/term's size and the gene universe tested. 5× means five times more shared genes than random. Tells strong hits apart when q-values are all vanishingly small.
P-value / FDR q-value
Is this pathway/GO term's overlap with the cluster more than chance? Upper-tail hypergeometric test, Benjamini-Hochberg corrected across every tested pathway/term (prefer the q-value -- it accounts for testing many at once).
Shared genes (Pairs within this cluster)
Number of curated genes the two diseases in that row have in common.
Similarity score (Pairs within this cluster)
Jaccard-based gene overlap between the two specific diseases in that row -- same metric as the main Shared-Gene Disease Pairs page.

Enriched Pathways (why this cluster is grouped, biologically)

Pathway ⇵ Source ⇵ Overlap genes ⇵ Fold enrichment ⇵ P-value ⇵ FDR q-value ⇵
AGE-RAGE signaling pathway in diabetic complications
AGER, AGT, CCL2, COL4A2, ICAM1, IL6, NOS3, SERPINE1, STAT3, TNF, VCAM1, VEGFA
 KEGG 47 / 101 4.6× 5.87e-21 5.41e-18 ✓ sig.
Lipid and atherosclerosis
ABCA1, AGER, APOA1, APOA4, APOB, CCL2, CCL3, CYBA, FASLG, HSPA1A, HSPA1B, ICAM1
 KEGG 69 / 216 3.1× 6.22e-19 4.29e-16 ✓ sig.
Interleukin-4 and Interleukin-13 signaling
ALOX15, ALOX5, CCL2, FASLG, ICAM1, IL6, MMP1, NOS2, PTGS2, SOCS3, STAT3, TNF
 Reactome 45 / 108 4.1× 8.70e-18 4.73e-15 ✓ sig.
Pathways in cancer
AGT, COL4A2, EDNRA, ESR1, FASLG, GSTM1, IFNG, IGF2, IL6, MMP1, NOS2, NQO1
 KEGG 115 / 533 2.1× 1.18e-15 4.48e-13 ✓ sig.
Complement and coagulation cascades
CLU, PLAT, SERPINE1, F2, F5, FGA, PLAU, F7, FGB, PROCR, PLG, CFH
 KEGG 37 / 88 4.1× 5.16e-15 1.73e-12 ✓ sig.
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
APOA1, APOB, APOE, IGF2, IL6, MMP1, ALB, F2, F5, FGA, AHSG, APOA5
 Reactome 45 / 125 3.5× 6.15e-15 2.04e-12 ✓ sig.
Platelet degranulation
APOA1, CLU, IGF2, SERPINE1, SOD1, VEGFA, ALB, F5, FGA, ITGA2B, ITGB3, TGFB1
 Reactome 44 / 123 3.5× 1.61e-14 4.79e-12 ✓ sig.
Cholesterol metabolism
ABCA1, ABCG5, APOA1, APOA4, APOB, APOC1, APOE, CETP, CYP27A1, LDLR, LPA, NPC1
 KEGG 27 / 51 5.2× 2.31e-14 6.62e-12 ✓ sig.
Post-translational protein phosphorylation
APOA1, APOB, APOE, IL6, ALB, F5, FGA, AHSG, APOA5, MIA3, APOL1, CST3
 Reactome 38 / 108 3.5× 1.82e-12 3.80e-10 ✓ sig.
HIF-1 signaling pathway
IFNG, IL6, NOS2, NOS3, SERPINE1, STAT3, TLR4, VEGFA, EDN1, PIK3CA, EPO, HMOX1
 KEGG 38 / 110 3.4× 3.49e-12 6.83e-10 ✓ sig.
Fluid shear stress and atherosclerosis
CCL2, CYBA, GSTM1, ICAM1, IFNG, NOS3, NQO1, PLAT, TNF, VCAM1, VEGFA, EDN1
 KEGG 42 / 141 2.9× 6.26e-11 9.37e-9 ✓ sig.
Malaria
CCL2, ICAM1, IFNG, IL6, TLR4, TNF, VCAM1, IL1B, TGFB1, SELE, CD40LG, IL10
 KEGG 23 / 50 4.5× 8.26e-11 1.21e-8 ✓ sig.
Chagas disease
CCL2, CCL3, FASLG, IFNG, IL6, NOS2, SERPINE1, TLR4, TNF, ACE, IL1B, PIK3CA
 KEGG 34 / 103 3.3× 1.97e-10 2.66e-8 ✓ sig.
African trypanosomiasis
APOA1, FASLG, ICAM1, IFNG, IL6, TNF, VCAM1, IL1B, SELE, IL10, NPPA, APOL1
 KEGG 19 / 37 5.1× 3.38e-10 4.32e-8 ✓ sig.
Hormone signaling
ADIPOQ, AGT, ESR1, IGF2, NPPB, STAT3, ITGAV, ITGB3, PIK3CA, AGTR1, ADRB3, EPO
 KEGG 52 / 219 2.3× 3.19e-9 3.16e-7 ✓ sig.

Enriched GO Terms (Biological Process, a second line of biological evidence)

GO term ⇵ GO ID ⇵ Overlap genes ⇵ Fold enrichment ⇵ P-value ⇵ FDR q-value ⇵
positive regulation of gene expression
APOB, BCL3, CCL2, CCL3, CLU, CRP, HSPA1A, HSPA1B, IFNG, IL6, LDLR, NOS3
 GO:0010628 101 / 504 3.1× 8.83e-25 2.66e-21 ✓ sig.
response to xenobiotic stimulus
ABCA1, ABCG5, ADIPOQ, AHR, CYBA, MTHFR, NPC1, SOD1, SOD2, TNF, EDN1, KCNK3
 GO:0009410 64 / 248 4.0× 4.31e-22 9.25e-19 ✓ sig.
positive regulation of transcription by RNA polymerase II
AHR, BCL3, ESR1, IFNG, IGF2, IL6, NEUROG3, NR1H4, PARP1, PPARG, SIRT1, SMARCA4
 GO:0045944 161 / 1,208 2.0× 5.70e-19 7.88e-16 ✓ sig.
regulation of blood pressure
AGT, EDNRA, NOS3, NPPB, PPARG, PTGS2, SOD1, SOD2, EDN1, ACE, ATP2B1, GNB3
 GO:0008217 33 / 83 6.1× 3.02e-18 3.76e-15 ✓ sig.
inflammatory response
AGER, ALOX15, ALOX5, CCL2, CCL3, CCL4, CNR2, CRP, CYBA, HDAC9, HP, HRH1
 GO:0006954 84 / 467 2.8× 1.05e-17 1.21e-14 ✓ sig.
kidney development
AGT, VEGFA, ACE, AGTR1, TCF21, BICC1, HAS2, LRP2, OVOL1, SLC34A1, SOX11, UMOD
 GO:0001822 43 / 146 4.5× 1.41e-17 1.60e-14 ✓ sig.
lipid metabolic process
ACACA, ABCA1, AIG1, ALOX15, ALOX5, APOA1, APOB, APOC1, APOE, CETP, CLU, CYP27A1
 GO:0006629 122 / 840 2.2× 2.33e-17 2.55e-14 ✓ sig.
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
AGT, CCL3, IGF2, SIRT1, TCF7L2, TNF, VEGFA, F2, IL1B, PIK3CA, TGFB1, IL17A
 GO:0051897 52 / 217 3.7× 1.08e-16 1.02e-13 ✓ sig.
positive regulation of miRNA transcription
AGT, IL6, PPARG, SMARCA4, STAT3, TNF, NOTCH3, TGFB1, IL10, NR3C1, SREBF1, TERT
 GO:1902895 26 / 56 7.1× 1.13e-16 1.05e-13 ✓ sig.
response to nutrient
ABCA1, ABCG5, ADIPOQ, AGL, PPARG, VCAM1, ABCG8, BCHE, EPO, LIPG, LTA, NOD2
 GO:0007584 27 / 63 6.6× 3.63e-16 3.09e-13 ✓ sig.
cellular response to lipopolysaccharide
ABCA1, CCL2, GBP3, IL6, NOS2, NR1H4, SERPINE1, TLR4, TNF, VIM, IL1B, PRPF8
 GO:0071222 47 / 187 3.9× 4.44e-16 3.73e-13 ✓ sig.
response to lipopolysaccharide
CNR2, FASLG, LOXL1, MPO, NOS2, NOS3, NQO1, SOD2, TLR4, TNF, VCAM1, EDN1
 GO:0032496 43 / 161 4.1× 7.41e-16 5.95e-13 ✓ sig.
blood coagulation
PLAT, F2, F5, FGA, ITGB3, PLAU, VKORC1, P2RY12, ANGPTL4, F7, FGB, GGCX
 GO:0007596 34 / 106 4.9× 2.01e-15 1.49e-12 ✓ sig.
negative regulation of apoptotic process
BCL3, HSPA1A, HSPA1B, IL6, MPO, NR1H4, PTGS2, SIRT1, SOCS3, SOD1, SOD2, TNF
 GO:0043066 85 / 524 2.5× 3.89e-15 2.75e-12 ✓ sig.
response to hypoxia
ADIPOQ, AGER, CBFA2T3, CYBA, EDNRA, MTHFR, NOS2, PLAT, SOD2, STAT3, TNF, VCAM1
 GO:0001666 44 / 176 3.8× 4.76e-15 3.29e-12 ✓ sig.

Pairs within this cluster, by significance

Disease A ⇵ Disease B ⇵ Similarity score ⇵ Shared genes ⇵ P-value ⇵ FDR q-value ⇵
Ischemic heart disease Myocardial ischemia 0.434 170 1.83e-290 1.92e-287 ✓ sig.
Kidney disease Kidney failure 0.175 101 6.97e-93 6.83e-91 ✓ sig.
Heart disease Myocardial ischemia 0.137 65 3.63e-65 2.58e-63 ✓ sig.
Atherosclerosis Myocardial ischemia 0.108 50 1.65e-48 8.81e-47 ✓ sig.
Kidney failure Myocardial ischemia 0.101 59 2.17e-40 9.70e-39 ✓ sig.
Ischemic heart disease Kidney failure 0.108 41 1.28e-36 5.22e-35 ✓ sig.
Heart disease Ischemic heart disease 0.120 34 6.64e-36 2.63e-34 ✓ sig.
Atherosclerosis Ischemic heart disease 0.111 29 2.73e-31 9.19e-30 ✓ sig.
Atherosclerosis Cerebrovascular disorder 0.115 21 1.54e-26 4.38e-25 ✓ sig.
Cerebrovascular disorder Heart disease 0.095 20 5.80e-23 1.33e-21 ✓ sig.
Heart disease Large artery stroke 0.092 19 4.56e-22 1.00e-20 ✓ sig.
Ischemic heart disease Large artery stroke 0.073 17 8.36e-18 1.50e-16 ✓ sig.
Cerebrovascular disorder Large artery stroke 0.079 12 9.98e-15 1.48e-13 ✓ sig.
Kidney failure Preeclampsia 0.036 12 6.36e-8 4.87e-7 ✓ sig.
Ischemic heart disease Preeclampsia 0.039 10 1.25e-7 9.18e-7 ✓ sig.
Atherosclerosis Erectile dysfunction 0.034 6 7.37e-6 3.93e-5 ✓ sig.
Erectile dysfunction Heart disease 0.030 6 2.37e-5 1.18e-4 ✓ sig.
Acetyl-coa carboxylase deficiency Erectile dysfunction 0.016 1 3.96e-3 5.01e-3 ✓ sig.
Preeclampsia Zaki syndrome 0.010 1 6.36e-3 7.64e-3 ✓ sig.
Kidney disease Peho-like syndrome 0.002 1 2.76e-2 2.94e-2 ✓ sig.