3 CHAPTER 3 62 Comparison between healthy controls and participants with migraine To determine whether the metabolite ratio model gives insight in disease pathology, we statistically compared the R2 correlations from healthy controls and participants with migraine. For singlemetabolite correlations,there were no significant differences between healthy controls and participants with migraine (Table S6). However, for the plasma/CSF ratios metabolite correlations, differences in R2 ratio were observed when comparing data of healthy controls and participants with migraine (Table S7, Figure S3). When comparing these correlations, significant differences after multiple testingcorrection(FDR < .05)wereobservedforthefollowingcombinations;L-Valine/L-Phenylalanine (FDR = .003), L-Arginine/S-Methylcysteine (FDR = .003), L-Alanine/L-4-hydroxy-L-proline (FDR = .015), L-Valine/L-4-hydroxy-L-proline (FDR = .025), L-Leucine/L-Phenylalanine (FDR = .028), and Gamma-L-glutamyl-L-alanine/L-4-hydroxy-L-proline (FDR = .041) Most relevant are probably L-Valine/L-Phenylalanine and L-Leucine/L-Phenylalanine, because the single-metabolite plasma/ CSF ratios between healthy controls and participants with migraine did not largely differ, where those of 4-hydroxy-proline and S-Methylcysteine seem to do, albeit not significant (Table S6). This means that the difference between healthy volunteers and patients with migraine in plasma/CSF R2 ratio is not merely driven by one metabolite but rather the mechanism behind it. For L-Valine/L-Phenylalanine ratio and the L-Leucine/L-Phenylalanine the ratio correlation was lower in migraine participants compared to that in healthy controls (Figure 3E-F).
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