ABSTRACT
We have established diagnostic thresholds of very long-chain fatty acids (VLCFA) for the differential diagnosis of peroxisomal disorders using the machine learning tools. The plasma samples of 131 controls and 90 cases were tested for VLCFA using gas chromatography-mass spectrometry following stable isotope dilution. These data were used to construct association rules and for recursive partitioning. The C26/22 in healthy controls ranged between 0.008 and 0.01. The C26 levels between 1.61 and 3.34 µmol/l and C26/C22 between 0.05 and 0.10 are diagnostic of X-linked adrenoleukodystrophy (X-ALD). Very high levels of C26 (>3.34 µmol/l) and C26/C22 ratio (>0.10) are diagnostic of Zellweger syndrome (ZS). Significant elevation of phytanic acid was observed in Refsum (t = 6.14, P < 0.0001) and Rhizomelic chondrodysplasia punctata (RCDP) (t = 16.72, P < 0.0001). The C26/C22 ratio is slightly elevated in RCDP (t = 2.58, P = 0.01) while no such elevation was observed in Refsum disease (t = 0.86, P = 0.39). The developed algorithm exhibited greater clinical utility (AUC: 0.99-1.00) in differentiating X-ALD, ZS and healthy controls. The algorithm has greater clinical utility in the differential diagnosis of peroxisomal disorders based on VLCFA pattern. Plasmalogens will add additional value in differentiating RCDP and Refsum disease.
Subject(s)
Algorithms , Machine Learning , Peroxisomal Disorders/diagnosis , Adolescent , Adult , Case-Control Studies , Child , Child, Preschool , Diagnosis, Differential , Fatty Acids/blood , Female , Gas Chromatography-Mass Spectrometry , Genetic Diseases, X-Linked/blood , Genetic Diseases, X-Linked/diagnosis , Genetic Diseases, X-Linked/genetics , Humans , Infant , Infant, Newborn , Male , Peroxisomal Disorders/blood , Peroxisomal Disorders/genetics , Phenotype , Phytanic Acid/blood , Young AdultABSTRACT
The rationale of the current study was to elucidate the contributing factors for the gender-based differences in total plasma homocysteine levels. A total of 413 subjects comprising of 293 men and 120 women were enrolled for the study. Chemiluminescence technology for vitamin B12, folate and total plasma homocysteine; ELISA for estradiol and 8-oxo-2-deoxyguanosine; Ellman's method for total glutathione; and PCR-RFLP analysis for the detection of methylene tetrahydrofolate reductase (MTHFR) C677T polymorphism were employed. No statistically significant differences were observed between the men and women in the distribution of age (p = 0.82), vitamin B12 (p = 0.23), folate (p = 0.36) and MTHFR C677T polymorphism (p = 0.35). However, the total plasma homocysteine levels were higher in men compared to women (28.4 ± 17.9 vs. 20.6 ± 13.6 µmol/L, p < 0.0001). In order to explain this gender differences in homocysteine, adaptive neuro-fuzzy inference systems (ANFIS) were developed to understand trivariate interactions among estradiol, glutathione and homocysteine. In the presence of adequate estradiol levels, inverse association was observed between glutathione and homocysteine. This association is lost when estradiol levels were inadequate. Estradiol was found to quench homocysteine mediated oxidative DNA damage. Irrespective of gender, combined deficiency of vitamin B12 and folate showed positive association with hyperhomocysteinemia and vice versa. Homocysteine reduction in response to vitamin status varied according to gender with men responding to folate and women responding to B12. To conclude, gender-differences in homocysteine are attributable estradiol mediated lowering of homocysteine that prevents inactivation of glutathione mediated oxidative defense in women.
