Table 1.
Methodological shortcomings and biases mitigated, addressed by checking the robustness of the results or disentangled by the design and analytical features used in the study
| Design/analytical feature | Selection bias | Information bias | Time-related bias | Confounding bias | |||||
|---|---|---|---|---|---|---|---|---|---|
| Healthcare access biasa | Prevalent user biasb | Misclassification of exposurec | Misclassification of outcomec, detection biasd | Protopathic bias (reverse causation)e | Immortal time biasf | Time-lag biasg, time-window biash | Confounding by indicationi | Residual confoundingj | |
| Adjustment for time since start of insulin use | – | – | Mitigated | – | – | – | Mitigatedg | – | Mitigated |
| Active-comparator approach | – | – | – | Mitigatedd | – | Mitigated | Mitigatedg | Mitigated | Mitigated |
| Cumulative exposure definition | – | – | Mitigated | – | Disentangled | – | – | Mitigated | – |
| Nationwide Nordic drug registers | Mitigated | – | – | – | – | – | – | – | – |
| Nationwide Nordic cancer registers | – | – | – | Mitigatedc | – | – | – | – | – |
| New-user design | – | Mitigated | Mitigated | – | – | Mitigated | Mitigatedh | Mitigated | – |
| Sensitivity analysis | Checkedk | – | – | Checkedc,k | – | – | – | Checkedl | |
| Time-varying exposure definition | – | – | Mitigated | – | Disentangled | Mitigated | Mitigatedh,m | Mitigated | |
aHealthcare access bias: differential degree of access to the healthcare among patients
bPrevalent user bias: risk of outcome is considerably higher or lower during the early period of drug therapy; inclusion of prevalent users may distort the association between the use of drug and outcome (including prevalent users may also introduce confounding)
cMisclassification (measurement) bias: inaccurate measurement or classification of key study variables, such as exposure, outcome or confounders: misclassification of exposure may arise from use of too simple (binary) exposure definition, especially for the complex pattern of use; misclassification of outcome may occur due to the use of incomplete records to identify events
dDetection bias: different probability of outcome detection during the follow-up in the compared groups
eProtopathic bias: symptoms treated by a drug are the manifestation of the yet-undiagnosed disease of interest
fImmortal time bias arises because of exclusion or misclassification of the follow-up time between the cohort entry and first exposure to a drug, before which the outcome of interest cannot occur
gTime-lag bias: compared treatments are commonly used at different stages of the disease (first-line therapy vs second- or third-line therapy)
hTime-window bias: unequal opportunity to become exposed between the compared groups owing to the time-window differential
iConfounding by indication: differences between compared treatments with respect to their indications (or contraindications)
jResidual confounding: the distortion that remains after controlling for confounding due to the unmeasured/uncontrolled confounders
kRestriction to the Nordic cohorts
lRestriction to the individuals with type 2 diabetes
mRestriction to the calendar period from 2000 onwards