Bridging in vivo and in vitro data from Japanese Toxicogenomics Project using network analyses

Figures & data

Table 1. Drugs with similar connectivity scores in the two networks are provided

acarbose	disopyramide	nimesulide
acetamidofluorene	Disulfiram	nitrosodiethylamine
acetaminophen	Doxorubicin	papaverine
acetazolamide	Enalapril	penicillamine
adapin	erythromycin ethylsuccinate	phenacetin
amitriptyline	ethambutol	phenobarbital
bendazac	ethinylestradiol	phenylanthranilic acid
benziodarone	Ethionamide	propylthiouracil
bromoethylamine	Etoposide	puromycin aminonucleoside
bucetin	Famotidine	quinidine
captopril	Fenofibrate	simvastatin
carboplatin	fluphenazine	sulindac
cephalothin	Flutamide	sulpiride
chloramphenicol	Gentamicin	tamoxifen
chlormadinone	Griseofulvin	tannic acid
chlormezanone	Hydroxyzine	terbinafine
chlorpheniramine	Imipramine	tetracycline
chlorpromazine	Labetalol	theophylline
chlorpropamide	Lomustine	thioridazine
ciprofloxacin	Lornoxicam	ticlopidine
clomipramine	mefenamic acid	tiopronin
colchicine	Meloxicam	tolbutamide
cyclosporine A	Metformin	triamterene
danazol	methyltestosterone	triazolam
dantrolene	Mexiletine	trimethadione
diltiazem	Nifedipine

High DILI drugs with similar connectivity scores are indicated in bold type.

Table 2. Genes which are not differentially expressed between the networks for at least 80% of the 18 high DILI drugs for which there is a statistically significant difference between the overall connectivity score for in vivo vs. in vitro networks based on the set of all genes

GENE (probe ID)	Prop.	GENE (probe ID)	Prop.	GENE (probe ID)	Prop.
(1397371_at)	0.944	(1378450_at)	0.833	Timm44 (1391940_at)	0.833
RGD1556401 (1368887_at)	0.889	ZNF474 (1378788_at)	0.833	Ogt (1394832_at)	0.833
(1381437_at)	0.889	ZIC3 (1384061_at)	0.833	(1395490_at)	0.833
RGD1564984 (1390265_at)	0.889	SNX12 (1390280_at)	0.833	(1396075_at)	0.833
TMEM164 (1396340_at)	0.889	Fam171b (1391313_at)	0.833	RGD1310414 (1396731_at)	0.833
Tspy1 (1370626_at)	0.833	(1391493_at)	0.833

The respective gene names (probe set IDs) and proportion of drugs with similar connectivity scores for that gene in the in vitro and in vivo networks.

Table 3. The top 5 clusters obtained from the DAVID Functional Annotation Tool

Cluster	Enrichment score	% of similar drugs
1	4.05	87
2	3.08	92
3	2.20	90
4	1.49	92
5	1.48	95

The last column shows the percentages of drugs for which the corresponding sub-networks were not significantly different.

Table 4A. Proportions of high DILI drugs for which the downregulated genes from Guzelian et al. common to the TGP data set are not differentially expressed

GENE (probe ID)	Prop.
MATN1 (1380579_at)	0.854
KIFC2 (1378197_at)	0.829
LRP5 (1380241_a_at)	0.756
Lrp11 (1397523_at)	0.659
DAP (1395881_at)	0.512
CLDN1 (1383946_at)	0.488
rnd3 (1377663_at)	0.463

For table legend, see Table 4b.

Table 4B. Proportions of high DILI drugs for which the differentially expressed genes (between cirrhotic and control groups) from Tugues et al. common to the TGP data set are not differentially expressed

GENE (probe ID)	Prop.
CAMK2G (1381936_at)	0.927
Ptger4 (1393638_at)	0.927
Mmp23 (1381451_at)	0.902
GATA3 (1382163_at)	0.902
GGT5 (1396208_at)	0.902
CDH1 (1386446_at)	0.878
ANXA1 (1394451_at)	0.878
Ankh (1386446_at)	0.829
GPR182 (1392664_at)	0.829

The respective gene names and proportion of drugs with similar connectivity scores for that gene in the in vitro and in vivo networks are provided.

Figure 1. In vitro and in vivo networks for cluster 4 and the drug phenylbutazone. Edges are displayed for gene pairs with connectivity scores (rescaled so that the largest score for the network is 1 in magnitude) greater than 0.5 in magnitude.

Figure 2. Box plots of the expression values for probe ID “1397371_at” under 8 high DILI drugs.