By Erik J. Landaas, MPH, PhD Student and Naomi Schwartz, MPH, PhD Student
Epidemiologic methods are central to the academic and research endeavors at the CHOICE institute. The field of epidemiology fosters the critical thinking required for high quality medical research. Pharmacoepidemiology is a sub-field of epidemiology and has been around since the 1970’s. One of the driving forces behind the establishment of pharmacoepidemiology was the Thalidomide disaster. In response to this tragedy, laws were enacted that gave the FDA authority to evaluate the efficacy of drugs. In addition, drug manufacturers were required to conduct clinical trials to provide evidence of a drug’s efficacy. This spawned a new and important body of work surrounding drug safety, efficacy, and post-marketing surveillance.[i]
In this article, we break down three of the more complex and often misunderstood concepts in pharmacoepidemiology: immortal time bias, protopathic bias, and drug exposure definition and measurement.
Immortal Time Bias
In pharmacoepidemiology studies, immortal time bias typically arises when the determination of an individual’s treatment status involves a delay or waiting period during which follow-up time is accrued. Immortal time bias is a period of follow-up during which, by design, the outcome of interest cannot occur. For example, the finding that Oscar winners live longer than non-winnersis a result of immortal time bias. In order for an individual to win an Oscar, he/she must live long enough to receive the award. A pharmacoepidemiology example of this is depicted in Figure 1. A patient who receives a prescription may survive longer because he/she must live long enough to receive a prescription while a patient who does not receive a prescription has no survival requirements. The most common way to avoid immortal time bias is to use a time-varying exposure variable. This allows subjects to contribute to both unexposed (during waiting period) and exposed person time.
Figure 1. Immortal Time Bias
Lévesque, Linda E., et al. “Problem of immortal time bias in cohort studies: example using statins for preventing progression of diabetes.” Bmj 340 (2010): b5087.
Protopathic Bias or Reverse Causation
Protopathic bias occurs when a drug of interest is initiated to treat symptoms of the disease under study before it is diagnosed. For example, early symptoms of inflammatory bowel disease (IBD) are often consistent with the indications for prescribing proton pump inhibitors (PPIs). Thus, many individuals who develop IBD have a history of PPI use. A study to investigate the association between PPIs and subsequent IBD would likely conclude that taking PPIs causes IBD when, in fact, the IBD was present (but undiagnosed) before the PPIs were prescribed. This scenario is illustrated by the following steps:
- Patient has early symptoms of an underlying disease (e.g. acid reflux)
- Patient goes to his/her doctor and gets a drug to address symptoms (e.g. PPI)
- Patient goes on to develop a diagnosis of having IBD (months or even years later)
It is easy to conclude from the above scenario that PPIs cause IBD, however the acid reflux was actually a manifestation of underlying IBD that was not yet diagnosed. Protopathic bias occurs in this case because of the lag time between first symptoms and diagnosis. One effective way to address protopathic bias is by excluding exposures during the prodromal period of the disease of interest.
Drug Exposure Definition and Measurement
Defining and classifying exposure to a drug is critical to the validity of pharmacoepidemiology studies. Most pharmacoepidemiology studies use proxies for drug exposure, because it is often impractical or impossible to measure directly (e.g. observing a patient take a drug, monitoring blood levels). In lieu of actual exposure data, exposure ascertainment is typically based on medication dispensing records. These records can be ascertained from electronic health records, pharmacies, pharmacy benefit managers (PBMs), and other available healthcare data repositories. Some of the most comprehensive drug exposure data are available among Northern European countries and large integrated health systems such as Kaiser Permanente in the United States. Some strengths of using dispensing records to gather exposure data are:
- Easy to ascertain and relatively inexpensive
- No primary data collection
- Often available for large sample sizes
- Can be population based
- No recall or interviewer bias
- Linkable to other types of data such as diagnostic codes and labs
Limitations of dispensing records as a data source include:
- Completeness can be an issue
- Usually does not capture over-the-counter (OTC) drugs
- Dispensing does not guarantee ingestion
- Often lacks indication for use
- Must make some assumptions to calculate dose and duration of use
Some studies collect drug exposure data using self-report methods (e.g. interviews or surveys). These methods are useful when the drug of interest is OTC and thus not captured by dispensing records. However, self-reported data is subject to recall bias and requires additional considerations when interpreting results. Alternatively, some large epidemiologic studies require patients to bring in all their medications when they do their study interviews (eg. bring your brown bag of medications). This can provide a more reliable method of collecting medication information than self-report.
It is also important to consider the risk of misclassification of exposure. When interpreting results, remember that differential misclassification (different for those with and without disease) can result in either an inflated measure of association, or a measure of association that is closer to the null. In contrast, non-differential misclassification (unrelated to the occurrence or presence of disease) shifts the measure of association closer to the null. For further guidance on defining drug exposure, please look at Figure 2.
Figure 2. Checklist: Key considerations for defining drug exposure
Velentgas, Priscilla, et al., eds. Developing a protocol for observational comparative effectiveness research: a user’s guide. Government Printing Office, 2013.
As alluded to above, pharmacoepidemiology is a field with complex research methods. We hope this article clarifies these three challenging concepts.
[i](Pinar Balcik, Gulcan Kahraman “Pharmacoepidemiology.” IOSR Journal of Pharmacy (e)-ISSN: 2250-3013, (p)-ISSN: 2319-4219 Volume 6, Issue 2 (February 2016), PP. 57-62)
Incremental Thoughts 