Title: Centile-based analysis of refractive development in the MiSight® 1 day Myopia Control trial
Authors: Daniel Ian Flitcroft(1,2); James Loughman(2); Baskar Arumugam(3); Arthur Bradley(3); Paul Chamberlain(3)
(1) Childrens University Hospital, Dublin, Dublin 1, Ireland
(2) Technological University Dublin, Ireland
(3) Coopervision, Inc., California, United States
Date: June 2020
Source: ARVO 2020 Abstracts - video presentation
Translating clinical trial results into clinical practice is made difficult by differences in participants vs patients and applying clinical trial analysis to a practice setting. The authors introduce the concept of using growth (centile) charts to monitor myopia progression and use these charts to assess the previously conducted MiSight 3-year data set to establish a good fit between the published outcomes from the clinical trial and representation on changes to centile chart tracking. This research establishes centile charts as a useful tool to use in clinical practice to determine successful outcome from a myopia control intervention.
Centile charts offer a simple way to monitor myopia development in an individual to determine whether they are likely to be slow or fast Progressors and whether a myopia control intervention is having an effect. However, while this provide promise, they are still at a relatively early stage of development.
Limitations and future research
- Meeting abstract so not fully peer-reviewed
- Growth charts and dataset restricted to European children - results don’t necessarily extrapolate to other nationalities / ethnicities
- Gives promise of easy to use myopia progression charts to:
- track progression of myopia in children
- help explain to parents the predicted change to myopia progression and outcomes from myopia management intervention
Clinical trials and clinical practice are different. Whereas clinical trials report averages, in clinical practice analysis is based on individual patients. Clinical trial participants enrol people who agree to participate in clinical trials and therefore are not truly representative of the broader range of the public that represent real life clinical patients. Clinical trials have fixed protocols, meaning that no adjustments to the treatment regimen are possible, while in clinical practice there is constant evaluation of treatment at each visit leading to decision on whether to continue, modify or stop a treatment on an individual basis. According to Hanney et al(fn) there is a 17 year lag between first evidence and standard clinical practice!
MiSight 1 day trial results:
- Myopic children 8-12yrs; -0.75 to -4.00DS; <1.00DC
- 3-year double masked randomised (MiSight vs Proclear single vision) trial, age, sex and ethnicity matched; 75.5% completed the trial (53 test, 56 control)
- 59% less change to refraction and 52% less change to axial length in test vs control
Questions that they wanted to look at in the current study:
- Was this group representative of what could be expected to see in clinical practice
- Does the average trial result translate to the public
- How to assess whether an individual patient is responding to the treatment
- How to convince parents that the treatment is worthwhile - i.e. child is still going to become more myopic
- How to tell if a patient is responding as expected
Growth (centile) charts have been established to predict future height and weight amongst other characteristics, and their widespread use makes them a simple to follow and understand concept. However, their use in eye care is relatively new. Consequently the authors created their own centile chart for refraction from 50,957 8-18 year olds extracted from 225,000 anonymised electronic European community health records. 9,092 contained refractive data over multiple visits.
The concept underlying use of centile charts is that change to predicted outcome can be identified from whether a child crosses centiles. Continued development can be assumed if their progress tracks the centile that they have previously been found to be following, crossing down to a lower centile indicates a reduction to rate of growth and crossing up to a higher centile indicates an increase to rate of growth. In myopia management terms these charts, if they could be reliably established, would provide a useful tool for assessing whether or not a myopia management intervention was providing a successful outcome.
Results from applying the developed centile charts to the MiSight dataset
Qu 1: Do MiSight 1 day study subjects cross down centile tracks (indicating reduction to myopia progression) as expected?
Answer: Yes they do (on average)
- Control participants on average followed the same centile with a roughly equal number cross up or down tracks.
- MiSight wearing participants on average jumped down tracks, with more overall jumping down tracks (slowing of myopia progression), however, a few (approx 25%) did jump up tracks indicating an increase in myopia progression rate when considered from a centile tracking perspective.
Qu 2: Does everyone respond?
- Some in the treatment group still fell into the high progression centiles meaning that some are poor responders
- Poor responders appeared similar in younger vs older participants, meaning age was not a factor for identifying poor responders
Qu 3: Is the treatment having an effect in a single subject?
Answer: Yes, the centile charts appear to provide the ability to track outcomes from individual participants, however it needs to be kept in mind that the true outcome for each individual is not known.
- In their presentation the authors showed one subject from the MiSight wearing group that showed stable refraction over 3-years and them tracking down a centiles, so good outcome
- However, in another individual subject from the MiSight wearing cohort, progression levels tracked the same centile over 3-years, indicating that progression was close to the expected untreated levels, so not a good outcome but also not a worse outcome
- and in another MiSight wearing individual they showed tracking up a centile despite treatment, meaning that progression increased relative to that expected from the centile chart
It needs to be kept in mind that centile charts are a model and people don’t necessarily follow models, so the displayed individuals that followed or tracked up centiles despite receiving the treatment may well have progressed even more had they not received the treatment - while the presented analysis helps shed some light on a useful tool to assess myopia progression and determine whether a treatment is providing a successful outcome, they still have some way to go to understand their limitations - in these cases whether the treatment didn’t work or instead whether the problem lies with the centile charts not being sufficiently representative across broad populations remains to be answered.
The authors presented how this kind of analysis could be summarised for use in practice in what they called a ‘refractogram’ with measured refraction, axial length and rate of progression charted over time to indicate whether the previously established centile for an individual patient was being tracked (expected outcome from no intervention), tracking up (worsening outcome) or tracking down (improving outcome).
- Results using developed centile charts when applied to the MiSight study data followed what they determined to be typical of that seen in Irish clinical practice - i.e. gives an indication that the MiSight study cohorts are representative of patients seen in typical practice and therefore suggests that the study outcomes should perhaps similarly translate across to practice.
- When evaluated using centile charts MiSight reduced myopia progression as indicated by an average shift to lower than expected age-matched progression rates
- However, this benefit is not seen in all individuals
- Centile charts offer a useful tool that can help establish whether a patient is likely to respond to a treatment or whether a patient is not responding to a treatment
- In this way they can provide a more useful tool to use in clinical practice than the analyses applied to clinical trials
- However, further work is needed to establish their reliability
Purpose: To employ centile analysis for assessing the treatment efficacy of a clinical trial for myopia control, and to quantify differences in the natural history of myopia progression in the treatment group, control group and conventional clinical practice.
Methods: Gender and age specific population centiles for refraction and annual progression were calculated for the 113 subjects recruited for the MiSight® 1 day trial (Chamberlain et al., OVS 2019) in Western trial sites (Portugal, United Kingdom and Canada). The reference population used for centile calculation comprised 4650 Irish children aged 8-17, from an anonymized sample of optometric health records where refraction data was available over multiple visits (mean 5.32, range 3-23).
Results: The partial MiSight control group showed no significant change in centile values of spherical equivalent refraction over three years (mean change -0.9, 95% CI -2.8 to 1.1) indicating that they were following the natural history pattern seen in the population based sample, whereas the treatment group showed a change of -10.7 (95% CI -12.7 to -8.7, Fig. 1). First year annual myopic progression in the control group was similar to that seen in the population sample with a mean centile of 58.4 (95% CI 53.3 to 63.5). In the treatment group the mean progression centile value was significantly lower at 32.6 in year 1 (95% CI 26.9 to 38.4), a difference that persisted over the three years of the trial (Wilcoxon, P= 0.027). Histograms of progression centiles show that the treatment group displayed a reduction in fast progressors, an effect present in both young (<= median age) and older subjects (> median age) (Kolmogorov-Smirnov two-sided test, treatment vs control young P < 0.00001, older group P < 0.0005, Fig. 2).
Conclusions: This analysis indicates that the MiSight lens can alter the natural history of myopia. There was a reduction in the proportion of fast progressors in both the younger and older treated subjects. Population based centile analysis offers the prospect of monitoring the treatment efficacy of myopia control interventions outside a clinical trial and allows individual clinical practice patients to be benchmarked against the results obtained during the MiSight trial.