Heterogeneity and publication bias
Inter-study heterogeneity was explored using the
Chi2-statistic, but the I2 value was calculated to
quantify the degree of heterogeneity across trials that could not be
attributable to chance alone. If heterogeneity was significant
(I2 > 75%), 3 strategies were used to
assess data validity and heterogeneity: (1) a subgroup analysis of
higher quality studies (quality score ≥10); (2) funnel plots to evaluate
publication bias (i.e., funnel asymmetry) with Egger’s test; and (3) a
meta-regression to assess the effects of covariates on the primary
outcome of interest.
A domain-based evaluation of risk of bias was performed in accordance
with the guidelines outlined in the Cochrane Handbook for Systematic
Reviews of Interventions Version 5.1.08 as previously
described7. Three authors (MM, MG, GN) subjectively
reviewed all studies included in this review and assigned a value of
‘critical’, ‘serious’, ‘moderate’ or ‘low’ to the following questions:
(Domain 1) Was the allocation sequence adequately generated? (D2) Was
allocation adequately concealed? (D3) Was the treatment adequately
classified? (D4) Were data affected by deviation from intended
intervention? (D5) Were incomplete outcome data sufficiently assessed?
(D6) Are reports in the study free of the suggestion of selecting
outcome measures or (D7) of selective outcome reporting?; ‘Risk of bias’
plots were performed using package ‘plotvis’ R-project, following the
Review Manager® Version 5.3 layout (The Cochrane Collaboration, Software
Update, Oxford, UK).