CLINICAL Workshop 3 — Sources of bias in case series, EPIDEMIOLOGY WORKSHOP patient cohorts, and randomised controlled trials

By far the most common type of original paper this means, they can make informed decisions as to published in the Hong Kong Medical Journal whether the reported results are applicable to their originates from a series of patients (cases) seen own practice settings. Response and participation in a certain health care setting (such as a hospital is usually not a problem for case series that purely and/or clinic). Not surprisingly, it is natural for describe clinical features (including laboratory research in clinical medicine to start with subjects findings), socio-demographic characteristics and seeking medical attention. The characteristics of treatments provided, as all such information is a series of cases may just be simply described and routinely collected for all attending patients and summarised, eg socio-demographic backgrounds, available for descriptive analyses. Nevertheless, if clinical presentations, outcomes, etc, but the series management of the disease involves invasive or risky of cases may also become the study subjects for investigations or interventions requiring specific conducting more elaborate research on prognosis consent (eg surgery), then it is expected that the and interventions. With a comparison or referent participation rate (eg acceptance of surgery) among group, they can also be utilised for studies looking all eligible subjects be reported. If the outcomes into risk factors or aetiology. during follow-up are also described, the follow-up rate should also be provided. Case series Information bias This study design refers to studies that mainly provide descriptive characteristics of the subjects Cases can be retrieved retrospectively or collected (the cases). Collection of detailed information on prospectively. Information on cases retrieved clinical presentations and summarising the data retrospectively is generally more objective, as it is systematically may provide support for identifying collected routinely in relevant medical records. A new diseases and guide clinical definitions, eg for the standard form for abstracting relevant information severe acute respiratory syndrome in 2003. Noting by someone blinded to the hypothesis (if any) should the socio-demographic characteristics of a series of provide unbiased information. However, missing cases, as well as the temporal and spatial distributions or incomplete information could be an issue. For can sometimes provide a clue to risk factors and prospectively collected information, it is desirable hence help generate a hypothesis. This can be tested to have standard protocols and/or forms to collect subsequently with more elaborate analytic studies. In the necessary information, to avoid missing data for purely descriptive case series, confounding is not a some patients. Furthermore, mechanisms should be concern, as the association between a certain factor built in to avoid excessive probing into particular and an outcome is not being studied. However, one aspects of a disease in certain patient subgroups, eg should still look out for possible selection bias (ways haemoptysis among chronic smokers. the subjects were identified, selected, and included). If all necessary data are not routinely collected in the medical records and abstracted in a standard manner, Prognostic studies in patient cohorts information bias may also become a concern. A case series can easily be extended to become a cohort of patients with the disease and then followed up to observe certain outcomes (prognosis), eg Selection bias recovery, recurrence, death. By definition, a cohort A case series consisting of all consecutive new study is an analytic study examining the association(s) cases seen in a hospital or clinic setting that fulfil between exposure(s) and outcome(s). Hence, simply predetermined inclusion and exclusion criteria describing the outcome(s) in a case series cannot be should be representative of cases encountered at regarded as a cohort study. A cohort study looking around the time the study is conducted. Since some at outcome(s) of patients can be called a prognostic diseases have seasonal variations, study periods study. As associations are being examined, spanning less than a year may not be sufficient and confounding should be addressed in addition to could mislead. Moreover, including all consecutive selection bias and information bias. new cases seen in a hospital or clinic may not be representative of all cases in Hong Kong, but that is more a concern of external validity for generalisation Selection bias of results. On the other hand, readers expect authors The recruitment of patients into the cohort for a to provide information on the specific hospitals/ prognostic study is basically the same as for a case clinics involved as well as the nature of the setting. By series, and hence selection bias on the part of the

478 Hong Kong Med J Vol 17 No 6 # December 2011 # www.hkmj.org # Clinical Epidemiology Workshop 3 # investigator(s) is usually not a major concern, as long as and thus distort (bias) the association between the clear inclusion and exclusion criteria are defined and all prognostic factor and the outcome of interest. In eligible cases are included. Response or participation theory, any known prognostic factor can have the rate among all eligible subjects should be reported in potential to confound associations between the situations where consent for specific investigations outcome and another prognostic factor. Hence, such and/or treatments is required, allowing readers to potential confounders should be considered and assess possible self-selection bias. Furthermore, as taken care of either in the recruitment process (using this type of study examines outcome(s) at time-points inclusion/exclusion criteria) or in the data analysis (by after the recruitment, loss to follow-up can be a major statistical adjustment). As a first step, information on concern. If patients lost to follow-up are systematically known prognostic factors (especially those that are different from those being successfully followed and well documented and major) should be available and if the proportion is substantial (eg >20%), the results collected. Regrettably, such information is not always can be seriously biased. fully available in prognostic studies depending on historical cohorts. In theory, a prospective cohort is likely to be much better in this aspect, especially Information bias when it is well planned after a thorough review of In theory, a cohort study recruits and classifies the literature to identify known prognostic factors. At subjects according to the presence or absence of least three categories of prognostic factors should be a study factor, but for prognostic studies, subjects examined for possible confounding: personal factors are recruited because they suffer from a certain (eg age, smoking, co-morbidity), disease status (eg disease. Factors affecting outcome(s) of interest stage, biochemical or functional impairments), and (ie prognostic factors) do not usually form the treatment(s) received. Confounders in each of these basis for selecting patients for recruitment. Hence, categories commonly affect disease prognosis. information on these factors (including potential confounding factors when specific associations are being examined) would normally have been Randomised controlled trials routinely collected in the usual medical care The gold standard to assess the efficacy or process and retrieved retrospectively (for historical effectiveness of interventions is the randomised cohort studies). Alternatively, in prospective cohort controlled trial (RCT). In the setting of clinical studies, relevant information could be specifically medicine, a RCT can be regarded as a special kind of assessed and recorded using standardised protocols. cohort study in which patient subgroups are followed Information bias on prognostic factors is usually not prospectively after having been randomly assigned a major concern, provided information is objectively to different interventions or exposures (including no recorded, its retrieval is standardised, and the intervention or placebo). Possible selection bias and retriever is blinded to the hypothesis being tested. self-selection bias can be present as in prospective In historical (retrospective) studies, such blinding prognostic studies; loss to follow-up being the most should also extend to the outcome status of subjects. important cause of this problem. In RCTs without Information bias on the outcome is a major proper allocation concealment, there can also be concern, unless it can be unequivocally objective, serious selection bias. As the intervention or exposure eg death from any cause. Hence, persons involved is randomly assigned, information bias at this stage in assessing outcomes should be blinded to the is unlikely to occur, although misclassification of the hypothesis under study, and the methods or actual exposure can still ensue due to non-compliance approaches used to ascertain the outcomes should be with the assigned intervention. On the other hand, standardised for all patients. The latter is of particular information bias with respect to outcomes is more importance, as the elapsed time to the event is liable to occur, especially if subjectively determined frequently used as the outcome variable in analysing and if adequate blinding (of the patient, medical the associations with prognostic factors. If a certain care provider, or outcome assessor) is not ensured. subgroup of patients with a given prognostic factor Theoretically, confounding is not an issue provided is being followed up more frequently or receiving that the randomisation process is effective, as the more investigations, it is inherently more likely that comparison groups would be very similar with respect the outcome of interest (eg recurrence of a cancer) to prognostic factors other than the intervention. will be detected earlier, even though that particular A summary table is available in the online prognostic factor does not influence the risk. version on www.hkmj.org.

Confounding Ignatius TS Yu Factors that independently affect outcome and at the Shelly LA Tse same time may be associated with the prognostic Clinical Epidemiology Group factor being examined can result in confounding, Hong Kong Medical Journal

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TABLE. Main sources of bias in studies on patient series* Study design Source of bias Selection bias Information bias Confounding Investigator Self (study Exposure(s) Outcome(s) Confounding subjects) factor(s) Case series + + + + N/A N/A Prognostic study + ++ + ++ + ++ Randomised controlled trial + ++ +/- ++ +/- +/- * N/A denotes not applicable, ++ major source, + minor source, and +/- unlikely

480 Hong Kong Med J Vol 17 No 6 # December 2011 # www.hkmj.org