The reproducibility of the different measures of neuropathy and interobserver agreement varies markedly between tests. This leads to the situation where the analysis for a clinical trial produces some results which are found to be significant whereas others are not, yet they might be assessing the same modality. To overcome this, Dyck and coworkers (43) pioneered composite scores such as the NDS and later the neuropathy impairment score (NIS). This allows an assessment of an alteration in function of several classes of nerve fibres, all of which are likely to be affected by diabetes. In the Rochester longitudinal study the NIS [LL] + 7 (vibration perception threshold [VPT] great toe, R-R variation to deep breathing, peroneal motor nerve conduction velocity, CMAP, and motor nerve distal latency, tibial motor nerve distal latency, and sural SNAP) have been shown to be 100% sensitive and specific in comparison with an abnormal VPT, which had a sensitivity of 27.8% (Table 4). Based on the findings of the Rochester study (43), a treatment effect of two points in NIS is deemed clinically meaningful. Therefore, to achieve a power of 0.90, about 140 patients need to be randomized to active and placebo arms for at least 2 years to detect a statistically significant difference at p = 0.05. However, if the primary end point is prevention of progression then the duration of the trial needs to be extended to about 4 years. A significant shortcoming of such composite scores arises when assessing the therapeutic benefits of agents which target a subclass of nerve fibres, e.g., NGF and C-fibres, where ideally one should focus on a small fibre abnormality (44).
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