14 Turner R.M.

Spiegelhalter D.J.

Smith G.C.

Thompson S.G. Bias modeling in evidence synthesis.

19 European Center for Disease Prevention and Control. Influenza case definition. Available at http://ecdc.europa.eu/en/activities/surveillance/eisn/surveillance/pages/influenza_case_definitions.aspx. Accessed May 1, 2011.

In the second step, we defined an idealized version of each included study. The idealized study is an imagined repeat of each study by means of a perfect design that could eliminate all sources of internal biases []. We identify the internal biases affecting each study by comparing the study carried out against its idealized version. External biases can be identified by comparing the idealized version of each study with the target setting of the meta-analysis. For example, if a study investigates the effect of vaccine in a population aged 50 years and older, an external bias arises because the target population of the idealized version of that study is older, that is 60 years and older. In a mini-protocol available in the bias checklist (available on the journal's Web site), the idealized study should be defined with respect to the population, which the researchers planned to study (eg, community-dwelling elderly), their planned comparison (eg, seasonal influenza vaccination vs. no vaccination), and the outcome, which they planned to measure. The idealized study with respect to different outcomes was defined as follows: for the laboratory-confirmed influenza outcome, the idealized study was restricted to the patients who, according to European Center for Disease Prevention and Control influenza case definition [], had at least one of the following clinical forms: ILI defined as sudden onset of symptoms, and at least one of the 4 systematic symptoms: fever, malaise, headache, or myalgia, and at least one of the 3 respiratory symptoms: cough, sore throat, or shortness of breath, and at least one of the laboratory criteria: isolation of the influenza virus from a clinical specimen, or detection of the influenza virus nucleic acid in a clinical specimen, or identification of the influenza virus antigen by direct fluorescent antibody test in a clinical specimen, or influenza-specific antibody response. For the ILI outcome, the idealized study was restricted to patients who had sudden onset symptoms, at least one of the 4 previously mentioned systematic symptoms, at least one of the previously mentioned respiratory symptoms, and a clinician judgment by a general practitioner or a nurse that the illness was due to a respiratory infection. For the hospitalization from influenza and/or pneumonia outcome, the idealized study was restricted to patients who had the diagnostic measurements of their disease such as laboratory tests and/or X-ray. For the all-cause mortality outcome, no extra specification was required for the outcome in the idealized study.