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    • The pre transplant and post transplant VMRs for methanol

    2018-10-23

    The pre-transplant and post-transplant VMRs for methanol, carbon disulfide, 2-butanone, 2-pentanone and limonene for all of our participants who underwent liver transplants (4 females (F1–F4) and 8 males (M1–M8)) are provided in Table 2. It should be noted that the number of days between collecting the pre-transplant and post-transplant breath samples is variable, because it is not possible to control when subjects are available or when a donor liver would be found. Only for one of the patients, F2, were we able to collect a pre-transplant breath sample just prior to surgery. However, and independent of when the pre- and post-transplant breath samples were taken, the results in Table 2 clearly demonstrate that the pre-transplant concentrations of these volatiles are, for the majority of patients, higher than the post-transplant levels for most patients. Limonene shows the largest average decrease and also decreased in all patients post-transplant. Post-transplant concentrations of limonene dropped to within the normal control range (median (LQ, UQ) being 2.3nmol/mol (1.9, 3.0)) within a number of days for all but one of the patients, M4, for whom limonene was found to be high even some months after transplant. In order to gain an insight on how the methanol, carbon disulfide, 2-butanone, 2-pentanone and limonene breath VMRs changed over a smo inhibitor of time after transplant, five patients (F2, F4, F5, M3 and M7) participated in a longitudinal study. The key result is that limonene VMRs dropped gradually following transplant surgery, as illustrated in Fig. 3. (The same data for limonene presented as normalised to the highest intra-individual value are shown in Supplementary Fig. 1.) This concentration time dependence was not observed for methanol, carbon disulfide, 2-butanone and 2-pentanone. Their VMRs were found to have dropped to within the normal range by the time of the first post-transplant measurement. Taken together, the box plots (Fig. 2), the ratio of the pre- and post-transplant VMR values and the significance values given above imply that ions at m/z 33, 81, 87 and 137 are the ones that are most diagnostically useful. This is confirmed by ROC curve analyses. Individually, limonene is found to provide the most predictive power (AUROC — 0.91 (standard error 0.04)). However, the best accuracy is achieved by combining the data from methanol, 2-pentanone and limonene. The VMRs for limonene, methanol and 2-pentanone were normalised to the highest patient value for that volatile. These normalised fractions were simply added with no weightings. Fig. 4 shows a ROC curve for the combined data. The AUROC is 0.95 (standard error 0.03) and achieves a sensitivity of 97% with a specificity of 70%. Volatile concentrations were examined for correlations with disease etiology. Owing to the small sample size and large number of etiologies, natural selection was only feasible for the 13 patients with ALD versus the other 18 patients. Limonene was higher (p=0.020) in the ALD group than the rest, with median (LQ, UQ) of 19.7nmol/mol (9.2, 63.9) for ALD versus 6.1nmol/mol (2.9, 16.6) for all other etiologies. Methanol, 2-pentanone, 2-butanone and carbon disulfide showed no statistically significant difference. Correlations between the 7 volatiles of interest in the putative marker set were examined both within the patient and the control group using a Kendall\'s tau-b test. In the patient group, there were 8 correlations with a significance score of <0.05. Results for all 21 correlations are shown in Supplementary Table 3. In the control group, only two were significant, limonene with m/z 135 (p=0.016) and 2-butanone with carbon disulfide (p<0.001). These were also found in the patient group. Limonene correlated significantly with 2-butanone (p=0.004), carbon disulfide (p=0.034), m/z 89 (p=0.001) and m/z 135 (p<0.001) but not with methanol or 2-pentanone. This suggests that the mechanisms for the presence of limonene and that of methanol and 2-pentanone are independent. 21 correlations were examined with no multiple-testing correction applied, therefore some correlations may be coincidental.