Table 1. Biochemical pathways with metabolites altered in the MIA mouse model of neurodevelopmental disorders.
| No. | Pathway | Measured metabolites in the pathway (N) | Expected pathway proportion (P=N/478) | Expected hits in a sample of 48 (P*48) | Observed hits in the top 48 metabolites | Fold- enrichment (Obs/Exp) | Impact (Σvip) | Fraction of VIP explained (% of 116.16) | Pathway normalized by single-dose suramin treatment |
|---|---|---|---|---|---|---|---|---|---|
| 1 | Purine metabolism | 48 | 0.1004 | 4.8201 | 11 | 2.3 | 28.19 | 24.3% | Yes (9/11) |
| 2 | Microbiome metabolism | 32 | 0.0669 | 3.2134 | 6 | 1.9 | 17.53 | 15.1% | Yes (6/6) |
| 3 | Phospholipid metabolism | 88 | 0.1841 | 8.8368 | 4 | 0.5 | 9.76 | 8.4% | Yes (4/4) |
| 4 | Bile salt metabolism | 4 | 0.0084 | 0.4017 | 3 | 7.5 | 9.23 | 7.9% | No (0/3) |
| 5 | Sphingolipid metabolism | 72 | 0.1506 | 7.2301 | 4 | 0.6 | 8.28 | 7.1% | Yes (4/4) |
| 6 | Cholesterol, cortisol, steroid metabolism | 19 | 0.0397 | 1.9079 | 4 | 2.1 | 8.08 | 7.0% | Yes (4/4) |
| 7 | Glycolysis and gluconeogenesis | 17 | 0.0356 | 1.7071 | 3 | 1.8 | 6.25 | 5.4% | Yes (3/3) |
| 8 | Oxalate, glyxoylate metabolism | 3 | 0.0063 | 0.3013 | 2 | 6.6 | 5.02 | 4.3% | Yes (2/2) |
| 9 | Tryptophan metabolism | 11 | 0.0230 | 1.1046 | 1 | 0.9 | 4.11 | 3.5% | Yes (1/1) |
| 10 | Krebs cycle | 18 | 0.0377 | 1.8075 | 2 | 1.1 | 3.58 | 3.1% | Yes (2/2) |
| 11 | Vitamin B3 (niacin/NAD) metabolism | 7 | 0.0146 | 0.7029 | 1 | 1.4 | 3.19 | 2.7% | Yes (1/1) |
| 12 | GABA, glutamate, arginine, ornithine, proline metabolism | 6 | 0.0126 | 0.6025 | 1 | 1.7 | 2.33 | 2.0% | Yes (1/1) |
| 13 | Pyrimidine metabolism | 35 | 0.0732 | 3.5146 | 1 | 0.3 | 2.24 | 1.9% | Yes (1/1) |
| 14 | Vitamin B2 (riboflavin) metabolism | 4 | 0.0084 | 0.4017 | 1 | 2.5 | 1.97 | 1.7% | Yes (1/1) |
| 15 | Thyroxine metabolism | 1 | 0.0021 | 0.1004 | 1 | 10.0 | 1.66 | 1.4% | Yes (1/1) |
| 16 | Amino-sugar and galactose metabolism | 10 | 0.0209 | 1.0042 | 1 | 1.0 | 1.61 | 1.4% | Yes (1/1) |
| 17 | SAM, SAH, methionine, cysteine, glutathione metabolism | 22 | 0.0460 | 2.2092 | 1 | 0.5 | 1.57 | 1.3% | Yes (1/1) |
| 18 | Biopterin, neopterin, molybdopterin metabolism | 1 | 0.0021 | 0.1004 | 1 | 10.0 | 1.56 | 1.3% | Yes (1/1) |
| 398 (0.8326 × 478) | 0.8326 | 40 (0.8326 × 48) | 48 | 116.16 | 100% | 94% (17/18) |
Abbreviation: VIP, variable importance in projection.
Pathways were ranked by their impact measured by summed VIP (ΣVIP) scores. A total of 48 metabolites were found to discriminate treatment, control, washout and MIA groups by multivariate partial least squares discriminant analysis (PLSDA). Significant metabolites had VIP scores of ⩾1.5. Eighteen (41%) of the 44 pathways interrogated had at least one metabolite with VIP scores ⩾1.5. The total impact of these 48 metabolites corresponded to a summed VIP score of 116.16. The fractional impact of each pathway is quantified as the percent of the summed VIP score and displayed in the final column on the right in the table. Single dose APT with suramin not only corrected purine metabolism but also normalized 17 (94%) of 18 metabolic pathway abnormalities that defined the MIA model of neurodevelopmental disorders.