MATERIALS AND METHODS

Retrieval strategy

Comprehensive literature retrieval was conducted using electronic databases such as PubMed, EMBASE, Google Scholar, Web of Science, and Cochrane Library (up to June 10, 2017). Medical subject headings (MeSH) (Emtree for EMBASE) and free-text words were adopted to balance comprehensiveness and accuracy. The following search terms were used: “Receptor, Epidermal Growth Factor” [Mesh], “Receptor Tyrosine-protein Kinase erbB-1”, “Transforming Growth Factor alpha Receptor”, “TGF-alpha Receptor”, “Epidermal Growth Factor Receptor Kinase”, “erbB-1 Proto-Oncogene Protein”, “erbB-1 Proto-Oncogene Protein”, “Receptor, Transforming-Growth Factor alpha”, “Receptor, TGF-alpha”, “c-ErbB-1 Protein, Proto-oncogene”; “Glioma” [Mesh], “astrocytoma”, “ependymoblastoma”, “ependymoma”, “glioblastoma”, “medulloblastoma”, “oligodendroglioma”, “optic nerve glioma”, “pontine glioma”, and “subependymoma”, and key words related to survival included prognostic, survival, predictive, outcome, and death. The references of retrieved articles were also screened for eligible studies.


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Inclusion and exclusion criteria

Inclusion criteria were as follows: 1) studies on pathological diagnosis of glioma in humans and investigation of EGFR expression in glioma; 2) studies containing hazard ratio (HR) or including survival data such as survival curves to estimate HR and its 95% confidence interval (CI); 3) studies published in English; 4) studies in which detection methods for EGFR were restricted to immunohistochemistry (IHC); and 5) randomized controlled trials, retrospective or prospective studies.

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Exclusion criteria were as follows: 1) non-human experiments; 2) letters, case reports, and reviews; 3) duplicated publications; and 4) inability to extract HR or necessary information.

Data extraction and quality assessment

All data were extracted independently by two authors (Junhong Li and Ruofei Liang). Disagreements were resolved by consensus with a third investigator (Yanhui Liu). The following data were extracted from the eligible studies: last name of the first author, publication year, region, study design, tumor type, assay, sample size, cutoff point, maximum follow-up time, HR, and its 95% CI.

HR and its 95% CI were extracted directly from the publications. If HRs and 95% CI were not available directly, they were calculated from the available survival data or extracted from the Kaplan–Meier curves by using the methods of Parmar et al12 and Tierney et al.13 If a study contained both univariate and multivariate analyses, both with HR, the HR provided by multivariate analysis was selected preferentially.

The quality of the eligible articles was evaluated on the Newcastle–Ottawa Scale (NOS), including assessments of patient selection, study comparability, follow-up time, and relevant outcome. NOS scores ranged from 0 to 9, with high-quality study defined as a score of >6.

Statistical analysis

HR and 95% CIs were used to evaluate the association between EGFR expression and OS in glioma. An HR of >1 indicated worse survival with elevated EGFR expression, and a 95% CI not overlapping 1 was taken to be statistically significant. Statistical heterogeneity of the included studies was assessed by I2statistics and chi-square test, and I2 value >50% or Pheterogeneity <0.05 indicated substantial heterogeneity. The random-effects model was used to estimate the pooled HR if heterogeneity appeared. Otherwise, the fixed-effect model was applied.14 All P-values were two-sided, and P<0.05 was considered to be statistically significant. Sensitivity analysis was also performed to evaluate the stability and reliability of the combinative results. The funnel plot with Begg’s test and Egger’s test was applied to evaluate publication bias. STATA 12.0 (StataCorp LP, College Station, TX, USA) was used to perform statistical analysis.