2 | Material and Methods
2.1 | Searches strategy and
selection
criteria
Our systematic review was performed and reported in accordance with
Meta-analysis Of Observational Studies in Epidemiology
(MOOSE)20 and the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA)21guidelines
We performed a systematic search in PubMed/Medline (1950 to Apr 2020),
EMBASE (1980 to Apr 2020), and Cochrane Central Register of Controlled
Trials (1950 to Apr 2020) for association between BCG vaccination and
Allergic disease by using relevant keywords including asthma, eczema,
rhinitis, BCG vaccines and other synonyms. The search method is provided
in appendix 1. We restricted the search to studies published in English
language and we screened bibliographies of relevant review articles to
ensure that all relevant studies were included.
Studies were first selected on the basis of their titles and abstracts
by two independent investigators. Then they retrieved full texts and
performed further screening when studies were deemed eligible. Studies
had to be either cohort or cross-sectional with participants data
included. Disagreements were resolved by discussion and, if necessary,
in consultation with a third, senior investigator.
2.2 | Data extraction and quality
assessment
Two authors extracted data independently using a standard data
extraction form. The following baseline characteristics were extracted
from the included studies: first author, year of publication, study
design, location in which the study was performed, number of included
participants and allergic disease. Studies were excluded when
participant data was not integrated.
Quality of all included trials was assessed by two authors independently
by using the Cochrane Collaboration risk of bias
tool.22 This tool evaluated biases from seven domains:
random sequence generation, allocation concealment, blinding of
participants and personnel, blinding of outcome assessment, incomplete
outcome data, selective reporting, and others. The risk of bias in each
domain was judged as low, high, or unclear. The overall risk of bias in
a study was classified as low if all domains had low risk; as high if
one or more domains had high risk, or as unclear
otherwise.12 Based on these standards, we classified
the studies into the following three grades: A, high quality and low
risk of bias; B, moderate quality and moderate risk of bias and C, low
quality and high risk of bias. Disagreements between the reviewers were
resolved by discussion with involvement from a third senior investigator
if necessary.
2.3 | Data analysis
We used STATA (version 12.0) to perform the data analysis, Odds ratios
(ORs) and their associated 95% confidence intervals (CI) were used to
assess the strength of association between BCG vaccination in early life
and the risk of getting allergic disease. Statistical tests were judged
statistically significant if the two-side P value was less than
0.0523. I² statistic were used for investigating
heterogeneity and if I² value was greater than 50%, it implied
statistical heterogeneity. We used random-effects modeling to perform
the meta-analysis if significant heterogeneity were performed and if
not, we used fixed-effects modeling.
If heterogeneity existed, we performed a subgroup analysis to
investigate whether the heterogeneity was related to the participant’s
race. Different ethnic background in different continents may be
considered potentially important to heterogeneity because of living
habit diversity. Funnel plots were used for displaying the publication
bias graphically, both specifically and officially with Egger’s test.