Discussion
smell impairment, CRSwNP, throat, pain, CRSwNP disease, nasal obstruction, nerve damage
SCARRING
Using data from SYNAPSE, this analysis evaluated the psychometric properties of the VAS and SNOT-22 in a blinded manner and determined the proportion of responders to mepolizumab using meaningful within-patient change thresholds for these measures, relevant to this population with very severe CRSwNP. Findings indicate that the VAS and SNOT-22 perform well and have acceptable psychometric properties in this very severe CRSwNP population. They also indicate that mepolizumab provided meaningful within-patient improvements in HRQoL versus placebo when added to standard of care. This indicates mepolizumab provides substantial clinical benefits in very severe CRSwNP.VAS item responses were selected across the range at Weeks 20, 24, and 52. While a higher proportion of responses were clustered at the upper versus lower end of the scale for all symptom VAS scores at baseline, this was expected owing to the very severe CRSwNP SYNAPSE eligibility criteria. No substantial floor or ceiling effects were seen during the treatment period except for a floor effect for loss of sense of smell across all time points. This was likely a result of the CRSwNP and the history of repeat nasal surgery in SYNAPSE patients, which can lead to permanent sense of smell impairment [All correlations between single VAS items were acceptable, supporting the use of two VAS composite scores (symptoms composite, and nasal symptoms and facial pain composite). Factor structure of the VAS composite scores, as determined by CFA, was acceptable with the CFI and SRMR statistics. Although Chi-square and RMSEA model fit were initially not acceptable, model fit improved following the incorporation of conceptually justifiable residual correlations. Although the residual correlation suggested some redundancy in the VAS items, which can lead to overweighting in composite scoring, these items were still included in the VAS composite scores based on their believed importance to patients. Regarding the Chi-square test, the improvement in model fit may have been due to the model’s tendency to reject the null hypothesis in large samples, such as the 407 patients included in this analysis, even when the hypothesized model shows trivial misfit.The VAS scores demonstrated acceptable internal consistency and excellent test–retest reliability. The VAS also demonstrated construct validity between corresponding VAS and SNOT-22 items, consistent with a priori hypothesized correlations. Correlations between the VAS and UPSIT, endoscopic NP and PNIF were weaker than a priori hypothesized correlations, which may be indicative of differences between objective or clinician-reported measures and daily patient reports of CRSwNP disease severity. In contrast, correlations between VAS scores and WPAI impairment-based scores and SF-36 PCS exceeded predictions.The VAS demonstrated acceptable validity based on several known-groups assessments and detected large effect sizes for all VAS scores using all anchors in patients determined to have improved. Psychometric analyses indicated a meaningful within-patient change threshold of − 2.5 points for overall symptoms, nasal discharge, and facial pain VAS and a threshold of − 3.0 points for nasal obstruction, loss of sense of smell, and mucus in throat VAS. This is consistent with previous studies indicating that a change of 2–3 points on a 0–10 VAS is considered a meaningful within-patient change [Psychometric analyses of SYNAPSE confirm the validity of the SNOT-22 total score, as previously reported [The analyses of patient responses to treatment using the VAS and SNOT-22 demonstrated that patients with CRSwNP experienced significant clinical benefits in symptom severity and HRQoL with mepolizumab versus placebo. Furthermore, the effect of mepolizumab on loss of sense of smell measured by the VAS was greatest in patients who had undergone one versus multiple prior surgeries. This may be related to the increased scarring and nerve damage associated with repeat surgeries, limiting the recovery of sense of smell [There were several limitations in the current analyses. Firstly, the psychometric analysis would have ideally used tailored ‘global impression’ anchor measures, specifically designed to evaluate meaningful change thresholds for the VAS and SNOT-22, rather than using the anchoring and triangulation of other outcome measures that were available at the time of this analysis. Use of an arbitrary overall symptoms VAS anchor may have overestimated changes in SNOT-22 score. Given this limitation, care was taken to justify the levels of change on each anchor considered a minimal improvement, where justification was based on clinical insight, published literature and patient input. However, we appreciate that our assumptions on what constitutes a minimal improvement are not guaranteed to precisely capture this level of change, and our chosen definitions may not be universally agreed upon. The suggested exploratory thresholds should therefore be confirmed in future research. Secondly, the same data were used to derive the meaningful within-patient thresholds and to determine the treatment response, which could be considered ‘overfitting’ the data. However, the psychometric analyses used data specific to the SYNAPSE trial in patients with very severe CRSwNP, therefore, the absolute values for respiratory threshold are likely not applicable in a less severe population. Furthermore, blinding the data to establish the thresholds mitigates the potential for overfitting. Thirdly, although the developer-recommended scoring of the SF-36v2 PCS and MCS has been contested, we did not explore alternate scoring options in detail [