Functional interpretation of metabolomics data as a new method for predicting long-term side effects: treatment of atopic dermatitis in infants

Running title: Pimecrolimus vs. desonide for treating AD in infants

Seul Ji Lee1,§, Sung-il Woo2,§, Soo Hyun Ahn3, Dong Kyu Lim1, Ji Yeon Hong1, Jeong Hill Park1, Johan Lim3, Mi-kyeong Kim4,*, Sung Won Kwon1,*

1College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea

2Department of Pediatrics, College of Medicine, Chungbuk National University, 52 Naesudong-ro, Heungdeok-gu, Cheongju 361-763, Korea

3Department of Statistics, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Korea

4Department of Internal Medicine, College of Medicine, Chungbuk National University, 52 Naesudong-ro, Heungdeok-gu, Cheongju 361-763, Korea


Supplemental Results

Results from MSEA and MetPA using Metaboanalyst.

For the metabolites that displayed differential altered levels in response to 1% pimecrolimus cream and 0.05% desonide cream, we applied metabolite set enrichment analysis (MSEA) and metabolic pathway analysis (MetPA). The results are presented graphically as well as in a detailed table. The table below shows the detailed results from MSEA and MetPA. Since we are testing many pathways at the same time, the statistical p values from enrichment analysis are further adjusted for multiple testings. In particular, the Total is the total number of compounds in the pathway; the Hits is the actually matched number from the user uploaded data; the Raw p is the original p value calculated from the enrichment analysis; the Holm p is the p value adjusted by Holm-Bonferroni method; the FDR is the p value adjusted using False Discovery Rate; the Impact is the pathway impact value calculated from pathway topology analysis. Significant results (P < 0.05) were summarized in tables.


Supplementary results 1.

MSEA result of metabolites showing altered levels after administration of 1% pimecrolimus cream

Total / Expected / Hits / Raw p / Holm p / FDR
Phenylketonuria / 12 / 0.392 / 2 / 0.0545 / 1 / 1
Transaldolase deficiency / 3 / 0.098 / 1 / 0.095 / 1 / 1
2-ketoadipic acidemia / 5 / 0.163 / 1 / 0.154 / 1 / 1
Purine nucleoside phosphorylase deficiency / 6 / 0.196 / 1 / 0.181 / 1 / 1
Maple syrup urine disease / 13 / 0.424 / 1 / 0.354 / 1 / 1
Breast cancer / 18 / 0.588 / 1 / 0.456 / 1 / 1


Supplementary results 2.

MSEA result of metabolites showing altered levels after administration of 0.05% desonide cream

Total / Expected / Hits / Raw p / Holm p / FDR
Cervical/colon/ovarian cancer / 1 / 0.0408 / 1 / 0.0408 / 1 / 1
Argininemia. Hyperargininemia, arginase deficiency / 3 / 0.122 / 1 / 0.118 / 1 / 1
Cancer (assorted) / 3 / 0.122 / 1 / 0.118 / 1 / 1
Adenosine deaminase deficiency / 4 / 0.163 / 1 / 0.154 / 1 / 1
Leukemia / 4 / 0.163 / 1 / 0.154 / 1 / 1
Argininosuccinic aciduria (asl) / 5 / 0.204 / 1 / 0.189 / 1 / 1
Ovarian cancer / 5 / 0.204 / 1 / 0.189 / 1 / 1
Thyroid cancer / 9 / 0.367 / 1 / 0.315 / 1 / 1
Phenylketonuria / 12 / 0.49 / 1 / 0.397 / 1 / 1
Maple syrup urine disease / 13 / 0.531 / 1 / 0.422 / 1 / 1
Chronic renal failure / 16 / 0.653 / 1 / 0.492 / 1 / 1


Supplementary results 3.

MetPA result of metabolites showing altered levels after administration of 1% pimecrolimus cream

Total / Expected / Hits / Raw p / -ln(p) / Holm p / FDR / Impact
Phenylalanine metabolism / 45 / 0.168 / 2 / 0.011 / 4.481 / 0.906 / 0.906 / 0.061
Riboflavin metabolism / 21 / 0.079 / 1 / 0.076 / 2.578 / 1 / 1 / 0
Glutathione metabolism / 38 / 0.142 / 1 / 0.133 / 2.013 / 1 / 1 / 0
Pentose and glucuronate interconversions / 53 / 0.198 / 1 / 0.182 / 1.705 / 1 / 1 / 0
Purine metabolism / 92 / 0.344 / 1 / 0.296 / 1.217 / 1 / 1 / 0.008


Supplementary results 4.

MetPA result of metabolites showing altered levels after administration of 0.05% desonide cream

Total / Expected / Hits / Raw p / -ln(p) / Holm p / FDR / Impact
Tryptophan metabolism / 79 / 0.394 / 3 / 0.006 / 5.108 / 0.484 / 0.484 / 0.044
Phenylalanine metabolism / 45 / 0.224 / 2 / 0.020 / 3.911 / 1 / 0.801 / 0.061
Retinol metabolism / 22 / 0.110 / 1 / 0.105 / 2.258 / 1 / 1 / 0.175
Alanine, aspartate and glutamate metabolism / 24 / 0.120 / 1 / 0.114 / 2.176 / 1 / 1 / 0
Arginine and proline metabolism / 77 / 0.384 / 1 / 0.324 / 1.128 / 1 / 1 / 0.016
Steroid hormone biosynthesis / 99 / 0.494 / 1 / 0.397 / 0.925 / 1 / 1 / 0.012