The findings of this large multicentre pooled concurrent diagnostic validity study reveal that IVCCM had diagnostic validity despite an imperfect reference standard for DSP, using both manual and automated corneal nerve quantification; CNFL was the optimal IVCCM variable and the estimate of performance in the primary analysis was conservative compared with sensitivity analyses that addressed the issue of the imperfect reference standard.
An objective imaging biomarker that can identify early-stage DSP (when interventions are most likely to be effective) and that can be used as an appropriate endpoint in the evaluation of putative therapies does not currently exist . Late diagnosis limits the potential benefits of early risk factor management in preventing neuropathy-related sequelae . The diagnosis of DSP itself is controversial as no definitive gold-standard testing exists aside from electrophysiological evaluation, which primarily identifies later-stage, large-fibre dysfunction and requires considerable specialist expertise, resources and time. In this context, IVCCM represents a rapid, non-invasive imaging endpoint for identifying early small fibre neuropathy. It has been extensively studied in small cross-sectional and cohort studies, which have established normative distributions , feasibility, reproducibility and the impact of variations in equipment and procedures.
As electrophysiological testing identifies later-stage rather than early-stage neuropathy, in the current analysis subclinical levels of neuropathy that were not classified as cases might a priori be expected to accentuate false-positives and impair test specificity. We believe this is the major reason for not achieving conventional standards of diagnostic performance and operating characteristics in this study. However, the performance and thresholds are sufficient to raise confidence in automated IVCCM as a diagnostic test . Further research must focus on evaluation of the influence of IVCCM on treatment decisions, possible roles relative to existing tests, its impact on clinical outcomes such as new onset symptomatic neuropathy and foot complications, its role in further evaluation of therapies for neuropathy and its economic impact.
The present study minimised common sources of bias in diagnostic studies, such as recruitment, spectrum and verification bias, but it had limitations. Though common protocols were used, centralised supervision of IVCCM image acquisition and analysis and electrophysiological testing were not implemented. As a cross-sectional analysis, it did not evaluate the predictive validity of IVCCM (a future goal of the consortium). Confirmation of a lack of age effect will require a larger older-adult sample size.
The diagnostic utility of IVCCM has been established in the largest cohort to date and the findings of this study further support the notion that IVCCM is an objective and simple diagnostic test for DSP. Further research must determine to what extent IVCCM can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.