Bias

Bias can be characterized as a product of systematic error in the design or conduct of a study.²¹⁵ The presence of bias will introduce a tendency of deviation from the truth, and thus threaten the validity

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of the study. Although there is an abundance of different biases, the majority of biases related to study design and procedures are classified in selection bias or information bias.

Selection bias occurs if there is a systematic error in the recruitment or retention of exposed vs. unexposed study participants.²¹⁵ Porta et al., claim that the requirement of informed consent in historical prospective cohort studies threaten these studies, as a large number of participants in reality makes it impossible to obtain an informed consent.²¹³ The requirement made by the Regional Committee for Medical and Health Research Ethics that all participants still alive were to be

informed about the study and given the possibility to withdraw from participating (passive consent), introduced a possible selection bias in our study. If those that withdrew their consent varied

according to exposure (TC treatment) or probability of outcome (e.g. if the majority of those that withdrew from participation had experienced a SC) this could introduce a systematic deviation of the results in our study. As only 0.38% men declined participation, the magnitude of this error, if it exists, is considered too small to hamper the results.

In cohort studies, selection bias usually relates to differential losses to follow-up, i.e. the study participants who are lost to follow-up differs from those that remain under observation. If those lost to follow-up have a different probability for the outcome, i.e. that there is not

independence between censoring and survival, this can cause bias of the incidence estimates, in particular the estimates of absolute cumulative incidence. As such, independence between censoring and survival is one of two fundamental assumptions in survival analyses.²¹⁵ Relative incidence estimates of within-cohort subgroups may however still be estimated if losses to follow-up are fairly similar between exposed and unexposed (a so-called compensating bias). Differential losses to follow-up mainly constitute a problem in prospective cohort studies with long-follow up time. In the present historical prospective cohort study censoring only occurred at death, emigration or study end. The distribution of TC treatment in those that emigrated (n=72 in paper III) was similar to the total study cohort, and thus differential losses to follow-up is negligible in our study. The second assumption in survival analyses is a lack of secular trends during the study`s accrual period.²¹⁵ If the characteristics of the participants changed during the accrual period or there were significant

changes in exposures (treatment), then bias of cumulative incidence estimates may be introduced.

Despite the modifications in TC treatment during the study (as described in chapter 1.4), the TC treatment in this study is still highly relevant today and thus enabling the estimates of cumulative incidences.

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Information bias in epidemiological research occurs when the definitions of study variables are inexact or when the data collection procedure is inaccurate.²¹⁵ This results in misclassification, defined as a systematic error in the classification of exposure and/or outcome status.

Misclassification can be non-differential (random) or differential (non-random). Non-differential misclassification is misclassification of exposure that is independent of the outcome or vice versa, while differential misclassification is misclassification of exposure or outcome that are dependent on status of the other.²¹⁵ In our study, misclassification of exposure variables could potentially occur in the process of establishing the clinical database; important information in medical records may have been overlooked, errors might occur whilst punching data into the clinical database, or the information reported in the medical journals was incorrect. These potential errors would cause non-differential misclassification as they are independent of the status of the outcome. These errors may leap in all directions, i.e. information of treatment given might be exaggerated (for example reported as four courses of chemotherapy while in reality none were given to this patient), or it might be understated (for example reported as no additional treatment given while in fact the patient received four courses of chemotherapy). The presence of non-differential misclassification will generally lead to an underestimation of the association between exposure and the disease, and it is an important reason why epidemiological studies underestimate effects. However, unpredictable outcomes may follow misclassification of confounding variables.²¹⁴ To minimize the chance of non-differential misclassification during data assembly, clinical data were plotted in a careful and thorough manner. As some degree of measurement error is inevitable,²¹⁴ this error could to some degree be reduced if two independent researchers collected the same data. This was however not feasible in our study due to a large amount of data to be collected. From personal experience, the chance for the exposure information in our study (i.e. the TC treatment information) to be flawed in medical records is minuscule.

The outcome information in our papers were obtained from two National Registries. The CRN is a cancer registry with very high completeness; through the Norwegian unique personal identification number, all hospital clinicians, pathology laboratories and general practitioners are instructed by law to report all new cases of cancer to the registry.²²² Additionally, the records in the CRN is supplemented with data from the NCoDR for all deaths registered with a cancer diagnosis to ensure completeness and validity, and with the national population registry for vital status. For information on cancer treatment, however, the quality of the CRN data are considered unreliable.²²⁴ The NCoDR also has a near-complete coverage.²²³ However, the quality of NCoDR has been