Criteria for considering studies for this review
Types of studies
We will include randomized controlled trials (RCTs). If outcomes from RCTs are not available, we will discuss findings from other study designs, such as cohort studies and case series.
Types of participants
We will include participants with keratoconus and will exclude any participants with non-keratoconic ectasia (e.g., post-LASIK [laser-assisted in situ keratomileusis]). We will consider keratoconus as defined by the included studies, and document whether corneal topography data and slit lamp data were used for diagnosis.
Types of interventions
We will include studies that compared intrastromal corneal ring segments with spectacles or contact lenses. We will include intrastromal corneal ring segments with or without photorefractive keratectomy (although its use in keratoconus is controversial and decidedly non-standard), and with or without corneal collagen cross-linking. We will include any type of ring studied (e.g., INTACS versus Ferrara).
Types of outcome measures
Outcome measures will assess variables associated with keratoconus disease progression.
Our primary outcome for comparison of treatments will be:
uncorrected distance visual acuity (UCVA) in the study eye at 12 months after intervention.
This will be considered as:
the proportion with UCVA 20/40 or better in the study eye; and
the mean change in UCVA from baseline in the study eye, measured on the Early Treatment in Diabetic Retinopathy Study (ETDRS) chart or equivalent.
Secondary outcomes of interest, assessed at three, six, 12, and 24 months, will include:
UCVA in the study eye at three, six, and 24 months, measured as: i) the proportion with UCVA 20/40 or better; and ii) the mean change in UCVA from baseline;
best-corrected distance visual acuity (BCVA) in the study eye, measured as: i) the proportion with BCVA of 20/40 or better; and ii) the mean change in BCVA from baseline;
corneal curvature in the study eye (mean change in diopters);
corneal thickness in the study eye (mean change in mm);
refractive error in the study eye (mean change of spherical equivalent in diopters);
contact lens tolerance (yes/no, or scale – as reported by study, categorized by type of contact lens worn); and
surgeons' experience with intrasomal corneal rings.
We will document and report adverse events reported by the included studies. Specific adverse events of interest include:
penetration of the ring(s) into the anterior chamber;
migration or extrusion of the ring(s);
other corneal complications, e.g., corneal abrasion, corneal scarring; and
loss of one or more lines of BCVA.
Search methods for identification of studies
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (latest issue), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to present), EMBASE (January 1980 to present), PubMed (1966 to present), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to present), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We will not use any date or language restrictions in the electronic search for trials.
See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), PubMed (Appendix 4), LILACS (Appendix 5), mRCT (Appendix 6), ClinicalTrials.gov (Appendix 7) and the ICTRP (Appendix 8).
Searching other resources
We will search the reference lists of included studies and use the Science Citation Index to identify potentially relevant studies that cited included studies. We will not search conference proceedings specifically for the purposes of this review, as RCTs presented at these meetings are searched by the Cochrane Eyes and Vision Group and included in CENTRAL.
Data collection and analysis
Selection of studies
Two authors independently will assess the eligibility of all records identified by the searches, beginning with titles and abstracts. Each author will classify each record as (1) definitely relevant, (2) possibly relevant, or (3) definitely not relevant according to the 'Criteria for considering studies for this review'. We will obtain full-text copies of each record classified as either (1) definitely relevant, or (2) possibly relevant.
Two authors independently will assess the full-text report(s) of studies and classify each study as (a) include, (b) unclear, or (c) exclude. We will resolve discrepancies at each stage by consensus. We will document all studies excluded after assessment of the full-text report and the reasons for exclusion. We will contact study investigators for studies classified as unclear for additional information to determine eligibility. If no response is received after four weeks, we will classify the reference based on the information available. For articles written in languages not read by the review authors, we will request assistance by colleagues to assess the studies for eligibility, and to translate the study information when needed.
Data extraction and management
Two authors independently will extract data using data extraction forms developed by the Cochrane Eyes and Vision Group, and modified for the specific purposes of this review. We will extract the following study characteristics for each included study: methods, participants, interventions, outcomes, and funding sources. One review author will enter the data into Review Manager 5.2 (RevMan 2012), and a second review author will verify the data entered. We will resolve discrepancies by discussion. We will contact study investigators to request missing data. If no response is received after four weeks, we will document that data were not reported and report the information available.
Assessment of risk of bias in included studies
Two review authors independently will assess the risks of bias in studies according to the methods described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Discrepancies between authors will be resolved through discussion.
We will consider the following parameters when assessing risk of bias in randomized trials: (a) selection bias (random sequence generation, adequacy of allocation concealment); (b) performance bias (masking of participants and study personnel); (c) detection bias (masking of outcome assessors); (d) attrition bias (completeness of follow-up, reasons for missing data); (e) reporting bias (selective outcome reporting); and (f) other potential sources of bias (such as funding source).
We will assess each included study for each parameter as having a "low risk of bias", a "high risk of bias", or an "unclear risk of bias" (insufficient information to permit judgment of low or high risk, or impact on risk of bias unclear). We will contact the study investigators when study methods are unclear or when additional information would facilitate making an assessment. If no response is received after four weeks, we will assess the risk of bias based on the information available.
Measures of treatment effect
The primary outcome for this review, UCVA at three months, will be assessed as both a dichotomous outcome and a continuous outcome. We will assess primary and secondary dichotomous outcomes as risk ratios with 95% confidence intervals. We also will report adverse events as risk ratios with 95% confidence intervals, when data are available.
We will report continuous outcomes as mean differences (with 95% confidence intervals) in the mean changes from baseline between groups, or comparing pre-intrasomal corneal rings results to post-intrasomal corneal rings results. When mean changes from baseline are not available, we will calculate the mean differences (with 95% confidence intervals) based on mean values at a follow-up time point, assuming baseline values between groups were distributed uniformly. When distributions are skewed, we will report the median and interquartile ranges, whenever sufficient data are available.
Unit of analysis issues
The unit of analysis will be the participant (i.e., one eye per participant). For studies in which both eyes of a single participant were included and analyzed separately, we will report whether appropriate adjustments for within person correlation of outcomes were performed.
Dealing with missing data
When data are missing or incomplete, we will contact study authors for additional information. If no response is received after four weeks, we will use the information available and document missing data. We will not employ imputation methods for missing data for the purposes of this review.
Assessment of heterogeneity
We will assess clinical, methodological, and statistical heterogeneity among included studies. We will assess clinical heterogeneity based on the characteristics of the participants, interventions, and outcomes of the included studies. We will consider study methods and risk of bias when assessing methodological heterogeneity. We will use the I2 statistic to examine statistical heterogeneity. We will consider an I2 value greater than 60% to indicate substantial statistical heterogeneity. When substantial clinical, methodological, or statistical heterogeneity is present, we will not conduct meta-analyses and instead, we will report the study results independently.
Assessment of reporting biases
We will examine reporting biases at the individual study level (selective outcome reporting) and review level (publication bias). We will assess selective outcome reporting for each included study by comparing study outcomes prespecified in study protocols, or clinical trial registrations, with those that were reported. We will examine publication bias based on the symmetry of funnel plots when ten or more studies are included in a meta-analysis.
When no substantial heterogeneity is detected, we will combine results in a meta-analysis. We will use a random effects model for meta-analyses including three or more studies. We will use a fixed-effect model when there are fewer than three studies. We will calculate the summary risk ratio with 95% confidence interval for dichotomous outcomes, and the summary mean difference between groups with 95% confidence interval for continuous outcomes. We will document study results that are not included in a meta-analysis as narrative summaries.
Subgroup analysis and investigation of heterogeneity
When sufficient data are available, we will conduct subgroup analyses based on receipt of additional therapy (e.g., participants who received intrastromal corneal ring segments only and participants who received intrastromal corneal ring segments plus photorefractive keratectomy).
When sufficient data are available, we will conduct sensitivity analyses to examine the impact of excluding unpublished studies, industry-funded studies, and studies assessed as having a high risk of bias, for any risk of bias parameter.