Verteporfin photodynamic therapy for neovascular age-related ...

16 MethodsPlan of analysisThe manual of operations recognised that the data set for the VPDT cohort study would havea complex structure, with varying numbers of visits/duration of follow-up across patients upto about eight visits/3 years of follow-up. It was also recognised that patients would be ‘nested’within groups of retinal specialists and DHs. Therefore, we planned to analyse the data set bymixed regression with multilevel modelling, an extension of conventional regression methodsto take into account statistical dependency between observations that are ‘clustered’ in the datastructure, for example observations within patients or patients within retinal teams.Follow-up of patients throughout the study period allowed repeated measurements of outcomesand changes over time to be described in detail. The main outcomes (BCVA, CS, HRQoL andlesion characteristics) were continuously scaled and could be analysed by mixed regressionwith multilevel modelling. We also planned to use similar models to quantify associationsbetween clinical outcomes and HRQoL. The analysis plan did not provide details of additionalanalyses but envisaged that outcomes might also be analysed in different ways, for example bydichotomising the change in BCVA to describe a deterioration of ≥ 15 ETDRS letters or not(a deterioration expected to occur in about 50% of participants) or using survival analysis todescribe the cumulative probability of a deterioration of this degree with increasing duration offollow-up.The analysis plan stated that, because of the complexity of the data set and the likelihood that thecomposition of the cohort would influence the nature of the analysis, a detailed plan of analyseswould be written after carrying out preliminary descriptive analyses. The preliminary descriptiveanalyses would characterise baseline clinical and treatment characteristics of patients recruited tothe cohort but not involve any comparative analyses. A number of baseline factors were expectedto influence outcomes independently following photodynamic therapy, including BCVA atpresentation, CNV composition and fellow eye comorbidities, and the analysis plan specified thatanalyses should take all of these factors into account.Consideration of predictors of outcome in the analysesAs described in Other predictors of visual function, known predictors of outcome were identifiedand collected. The use of adjunctive treatments was also documented, although it was not knownif these would influence outcome. The plan of analysis recognised that it would be importantto take into account differences in these predictors between subgroups that were of interestto compare.Estimating the effectiveness and cost-effectiveness of verteporfinphotodynamic therapyThe objective of estimating effectiveness and cost-effectiveness required comparisons to bemade with untreated patients. At the outset, we recognised that the lack of a concurrent controlgroup was an important limitation of the study and a number of strategies were discussed toestimate outcomes for untreated patients. We proposed to use the following three methods and toinvestigate the impact of using different methods on estimates of effectiveness, cost-effectivenessand cost–utility:(a) Extrapolation from trial data Existing trials of VPDT provide estimates of effectiveness.Longitudinal data for BCVA, CS and HRQoL outcomes also exist from a previouslyconducted UK-based clinical trial of CNV of AMD in which the intervention was noteffective at the specified outcome points. 42 Self-reported use of HSS resources in relation toAMD were also collected in the VPDT cohort study (see Appendix 2). We proposed to use