681 analyses have been performed to answer this question [4, well: year of publication; type of ventilator used for HFV 5, 6, 7, 8]. Pooled estimates of pulmonary outcomes failed (Sensormedics 3100A ventilator versus other); ventilation to show clinically relevant differences among HFV and strategies applied in the HFV and CMV treatment groups CMV [7]; however, signiﬁcant heterogeneity existed be- were obtained as previously described [4]; time on CMV tween studies included in these meta-analyses. In a recent before study initiation; gestational age and birth weight; cumulative meta-analysis we identiﬁed improvements and outcome rates in the control population were taken as of the conventional treatment of IRDS and ventilation proxy for baseline disease severity in the source popula- strategies applied in both HFV and CMV as important tion. The Sensormedics ventilator was singled out because sources of heterogeneity [4]. These associations could previous research suggested better performance compared be confounded by other explanatory variables. Although with other oscillator ventilators [2, 4]. a meta-analysis may pool results from randomized trials, differences among trials will not be randomly or inde- pendently distributed. A meta-analysis constitutes an observational study of trials, subjected to bias inherent to Statistical analysis observational research. In a meta-regression analysis it is possible to adjust for confounding covariates. A number All data were extracted according to the intention-to-treat of alternative hypotheses have been formulated to explain principle. The number of patients surviving without heterogeneity between trials: chronic lung disease was subtracted from the total number of randomized patients in each treatment arm to calculate 1. The observed regression of the cumulative relative the composite outcome of death or CLD. To calculate the risks to the level of unity was due to publication bias. risk of CLD, the number of surviving patients was put in 2. Use of the Sensormedics ventilator resulted in better the denominator. Publication bias was assessed by visual results in HFV treated patients. appraisal of symmetry of funnel plots and performing rank tests. Smaller studies could show different results 3. A prolonged ventilation on CMV before initiating HFV treatment could reduce the beneﬁts of HFV. than larger studies which could suggest publication bias, but in fact was caused by systematic differences among 4. In subgroups of more premature neonates with lower studies; therefore, an analysis of publication bias stratiﬁed birth weight with a higher susceptibility for CLD, HFV for ventilation strategies was performed to determine could result in better pulmonary outcome. whether the observed association between the inverse of 5. With outcome rates increasingly representing more se- the standard error with the risk ratio was confounded by vere disease, HFV could have an increasing advantage ventilation strategies. Meta-regression analysis was used over CMV [9, 10]; therefore, we used meta-regression to evaluate other hypotheses. The dependent variables, analysis to better estimate relative treatment effects RR of CLD and RR of CLD or death, were natural log through adjustments for factors that could explain trial transformed to linearize the regression models. Individual heterogeneity. studies were weighted by inverse variances of relative risks of outcomes of interest so that the more precise studies had more inﬂuence in the analysis. Firstly, linear regression analyses were applied to explanatory variables. Methods Secondly, linear regression analyses with continuous covariates were conducted stratiﬁed by HLVS, LPVS, Trials were included based on a previous meta-analysis and use of surfactant. Finally, multivariable linear re- that we had conducted [4]. The same search strategy, as gression analyses were performed to calculate adjusted well as the same inclusion and exclusion criteria as in our contributions of different explanatory variables of rivalling previous meta-analysis, were used for an update, yield- hypotheses to changes in RR. The relative effects of ing two more studies that could be included for this meta- covariates were evaluated by relative risk ratios (RRR). regression analysis. Validity of studies was assessed by cri- A relative risk ratio quantiﬁes the relative change in RR teria published by Jadad et al. [11]. The validity was gener- that is associated with a speciﬁed change of a covariate. ally deemed as high with adequate allocation concealment For continuous variables the RRR was calculated for the in all trials. Blinding of treatment was not possible due to ranges of minimum and maximum values of covariates the nature of the interventions. that were reported in trials. For example, the RRR for Data extraction was performed as has been reported in year of publication was calculated by using the range our previous meta-analysis. The following outcome meas- between the publication year of the ﬁrst year and the ures were used: mortality, chronic lung disease (CLD) publication year of the last included trial. The RRR for as deﬁned by supplemental oxygen need or ventilator year of publication thus estimates the relative change in dependency at the age of 30–36 weeks post-menstrual. RR due to the difference in years of publication between A number of explanatory variables were extracted as the ﬁrst and last trials. All analyses were conducted using