The sensitivities of these techniques have also been questioned, particularly in reference to more recent methodologies, such as polymerase chain reaction (PCR).
29 More recent methodologies include Pd-catalyzed three-component methods, 30– 33 addition of alkylchloroaluminum amides to nitriles, 34 aryne insertion into thioureas 35 and ytterbium-catalyzed addition of amines to nitriles.
Although initial studies (for review see [ 14]) were implemented using rather crude stimulating devices, some of the more recent methodologies allowed quantitative evaluation of this sensory modality [ 14, 15, 20, 21].
Hence, although the FDA guidance infers that PRO instruments should aim to measure the adverse consequences of treatment separately from the effectiveness of treatment, more recent methodologies would support efficacy (or effectiveness) data being collected from the same dataset as safety, and may in fact improve the utility of the information [ 33].
A more recent overview of methodology used to analyze GC content variation within genomes can be found in Bernaola-Galvan et. al., [ 30], and a study of how intra-genomic GC content variation affects codon usage is described by Daubin et. al. [ 31].
More recent improvements to the methodology have come from the work of Quaas [ 11] and Meuwissen and Luo [ 12], and this efficient algorithm is currently implemented in the software package ASReml [ 13].
A few more recent controlled studies — with better methodology than the older research — suggest that the answer is no.
However, many earlier studies were based on bacterial identification using culture methodology; but more recent studies suggest that molecular techniques may be more sensitive.
Using similar methodology, a more recent study made similar extrapolations from data collected in Utah and Colorado, arriving at a total population figure slightly less than one million [ 5].
Ten years later Bern et al. published an update of this review using similar methodology, including more recent studies, and estimated children to have 2.6 episodes of diarrhea/year [ 7].
