Finally in the context of

Finally, in the context of this adipose specific FABP4 transgenic (over expression) mouse model phenotype, it is essential to discuss the caveats of this animal model. In the last five years several reviews have highlighted the advantages and disadvantages of the different promoters (for example FABP4 vs. adiponectin) for adipose specific gain and loss of function studies including the following: (i) physiological implications of leaky expression in non-adipose tissues and over expression and (ii) ectopic gene position and copy number (Wang et al., 2010; Kang et al., 2014; Jeffery et al., 2014; Wang et al., 2014; Lee et al., 2013). Recently it has been demonstrated that the FABP4 and adiponectin Cre produced very similar phenotypes in side by side comparisons (Kim et al., 2016). However, these qualifications we discussed above need to be considered in the interpretation of any transgenic over expression model.
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Conflicts of Interest
Acknowledgements
Introduction Isoniazid is a first line antituberculosis agent recommended for treatment of children with tuberculosis (TB). Its conversion is catalyzed by arylamine N-acetyltransferase (NAT) isoenzyme 2 (NAT2) in phase II xenobiotic metabolism. NAT2 is central to detoxifying many environmental-, industrial-, and food-based arylamines and hydrazines. NAT2 catalyzes the reaction of acetyl-CoA and isoniazid (substrates) to produce CoA and N-acetylisoniazid. NAT2 single nucleotide polymorphisms (SNPs) identified in adults led to classification of individuals as slow and rapid acetylators. Specific SNPs could be associated with changes in enzyme catalytic activity, as defined by enzyme reaction kinetic constants in liver tissue (Blum et al., 1991; Fretland et al., 2001). The elimination of isoniazid from the body is a combination of NAT2 metabolism and direct elimination of parent compound, with parent isoniazid elimination in urine of up to 37%. However, in adult patients 88% of systemic clearance variability has been linked to NAT2 SNPs (Kinzig-Schippers et al., 2005). While the ontogeny of phase I Fulvestrant is well established, the age-dependent maturation changes in phase II enzymes such as NAT2 are still poorly understood. This is important since isoniazid peak concentrations and 0–24h area under the concentration-time curves (AUC0–24) are major determinants of cure rates, speed of sterilizing effect, and acquired drug-resistance, in TB patients (Chigutsa et al., 2015; Pasipanodya et al., 2013, 2012; Pasipanodya and Gumbo, 2011; Gumbo et al., 2014; Dheda et al., 2014). There could be an age-dependent difference in systemic clearance of isoniazid in children, however, the effect of maturation, or other pediatric factors, on NAT2 enzyme kinetics has hitherto not been investigated (Jeena et al., 2011; Rey et al., 2001). Here, we identified the rate of production of N-acetylisoniazid and the rate of elimination of isoniazid in children enrolled in the prospective PHATISA study (Hiruy et al., 2015) and investigated the possible effects of NAT2 SNPs, measures of body-size, age, and nutrition status, in altering NAT2 reaction kinetics and isoniazid elimination rate constants. Human growth and physiological maturation are non-linear processes, with discordant changes that have direct effect on drug pharmacokinetics (Kearns et al., 2003). Indeed, in recent years it has become evident that even in adults the relationships between different pharmacokinetic parameters and covariates such as age and weight are not only non-linear, but have high order interactions, with data zones of discontinuity in the relationships (Hall et al., 2011, 2013; Jain et al., 2013). Thus, standard statistical analyses could be limited on several fronts, including reliance on linear analyses and the restrictive normality, collinearity and sampling assumptions needed for valid inference. In 2012, Kiser et al. used standard statistical and pharmacokinetic approaches and identified that NAT2 genotype and child\'s age were associated with isoniazid clearance in South African infants. With the slow acetylator genotype, weight adjusted clearance was unchanged from week to week 12 but increased 28% in week 84; while for rapid acetylators it increased 13% from week to week 12 but then decreased by 23% in week 84 (Kiser et al., 2012). In other words, the changes were non-linear. Isoniazid elimination is from a combination of NAT2 metabolism and loss of parent compound in urine, which could account for the complex picture observed. Here, we used non-linear science to identify the role of maturation, weight, and NAT2 SNPs on xenobiotic metabolism in children (Campbell, 1987; Campbell et al., 1985; Dokoumetzidis et al., 2002). We applied artificial intelligence (AI)-based non-linear analyses to investigate NAT2 maximum velocity (Vmax) and affinity (Km) during the first decade of life in children with TB. We were interested in determining relationships that could be used to scale from the level of enzyme-based chemical reactions to the whole organism (patient) in the clinic, to allow for direct translation.