Exposure Definition and Measurement in Observational

Comparative Effectiveness Research

Prepared for:Agency for Healthcare Research and Quality (AHRQ)

www.ahrq.gov

This presentation will: Propose a definition of exposure that is consistent with the

clinical/ conceptual basis for the research question Provide a rationale for choice of exposure time window Describe the proposed data source(s) and explain how they are

adequate and appropriate for defining exposure Provide evidence of validity of the operational definition of

exposure with estimates of sensitivity, specificity, and positive predictive value, when possible

Support the unit of analysis chosen for exposure measurement (e.g., person-months of exposure) and discuss the trade-offs for alternative units of measurement

Address issues of differential and nondifferential bias related to exposure measurement and propose strategies for reducing error and bias, where possible

Outline of Material

In epidemiology, the term exposure can be broadly applied to any factor that may be associated with an outcome of interest, including: Primary explanatory variable of interest Other variables associated with the outcome (confounders

or effect modifiers) “One-time” interventions may only require determining if and

when (surgery or vaccine administration). Pharmacological or other longer term exposures (educational

interventions) involve measuring intensity (dose, frequency, duration).

Data elements define how exposure is measured (often proxy indicators such as dispensing records).

Introduction

Linking exposure measurement to study objectives: The conceptual basis of a study is the foundation

for developing an operational definition of exposure.

Distinguish short-term use from long-term use. Examining the exposure/outcome relationship:

Lay out the theoretical and biological link between exposure and the outcome of interest (drawn from conceptual framework).

If the primary exposure of interest is a medication, can describe how pharmacology/pharmacokinetics/ pharmacodynamics informed the exposure definition.

Conceptual Considerations for Exposure Measurement

Examples of Exposure/Outcome Relationships

Timeline of Exposure, Induction Period, Latent Period, and Outcome

Adapted from White E, Armstrong BK, Saracci R. Principles of exposure measurement in epidemiology. 2nd ed.New York, NY: Oxford University Press Inc.; 2008. p. 18. By permission of Oxford University Press (www.oup.com). Copyright © 2008. All rights reserved.

Existing electronic data A consistent and accurate way to identify the exposure

in the dataset? One code or multiple codes? Variable code types?

If too broad, can lead to exposure misclassification Validation methods to justify decisions

Prospective data collection Abstraction of paper medical records Characteristics of exposure and patient population can

influence validity Self-reported information, recall (timeframe,

frequency)

Data Sources for Exposure Measurement

Time window of exposure Defined as the period of time during which the exposure is

having its effects relevant to the outcome of interest Must consider the induction and latent periods when

defining the exposure time window Practical limitations of study data should be acknowledged

and sensitivity analyses performed to evaluate robustness of the results to the time window

Unit of analysis Largely dictated by the nature of the intervention Can be defined at the patient level if it does not vary with

time Person-time can be used when exposure status varies

over the course of the study period

Creating an Exposure Definition

Measurement scale The more precise, the less measurement error

Dichotomous variables Continuous covariates (typically used when there

is a dose-response relationship) Categorical variables (may introduce less bias)

Precision of exposure measure Source of data can limit precision (dispensing records

vs. actual usage) Be aware of the benefits and limitations of the data

source, and avoid exposure misclassification

Creating an Exposure Definition

Dosage and dose-response The cumulative dose (total amount of exposure over a

specified time period) is often optimal for adequately defining exposure (and existence of a threshold effect). Frequency, amount/dose of each occurrence, and

duration of exposure It is applicable to medications and health services

interventions. The definition of exposure must be specific to the exposure

of interest and must avoid misclassification due to the availability of other dosage forms or routes of administration.

Behavioral factors (medication adherence) might modify the effect of the observed association.

Creating an Exposure Definition

Changes in exposure status Pertains particularly if patients switch between active

exposures when two or more are being investigated Determining “spillover” effects or biological effects

Exposure to multiple therapies Lack of control over all medications used in a study Exposure to other medications not randomly

distributed Must consider the influence of other exposures on

the outcome, not just primary exposure Multiplicative/additive effects

Additional Exposure Considerations

Differential misclassification: when an error in exposure measurement is dependent on the event of interest (leads to biased estimates towards or away from the null)

Nondifferential misclassification: when errors in measurement of exposure are proportionally the same in both the group that does and does not experience the outcome of interest Sources of error: failure to account for changes in

exposure, a short exposure time window, measurement during induction/latent periods, and using services not captured in the data source

Measurement time bias: bias in measurable exposure times

Immortal time bias: when person-time is inappropriately assigned to an exposure category

Issues of Bias

To operationalize exposure in comparative effectiveness research using observational data: The clinical pathways and conceptual framework that

motivate the comparative effectiveness research question should be the guide.

The characteristics of the exposure and the outcome of interest must be known.

Researchers must be aware of the level of detail on the exposure in a dataset and the options for characterizing it.

Researchers must deliberate the approaches used to limit the potential for bias and measurement error.

Conclusion

Summary Checklist (1 of 2)

Guidance Key Considerations

Propose a definition of exposure that is consistent with the clinical/conceptual basis for the research question

• Consider the physiological effects of the exposure/intervention when creating an operational definition of exposure

• Determine the most suitable scale for the measurement of exposure

Provide a rationale for choice of exposure time window

For medications, consider factors such as dose, duration of treatment, pharmacodynamic/ pharmacokinetic properties (e.g., half-life), and known or hypothesized biological mechanisms associated with the medication of interest

Describe the proposed data source(s) and explain how they are adequate and appropriate for defining exposure

 

Summary Checklist (2 of 2)

Guidance Key ConsiderationsProvide evidence of validity of the operational definition of exposure with estimates of sensitivity, specificity, and positive predictive value, when possible

• If there are no validation studies to define the exposure of interest, use measures and definitions that have been most commonly reported in the literature to facilitate comparison of results

• Alternative definitions could be developed and used in addition to a “commonly used” definition for exposure, particularly if there are reasons to suspect there may be more accurate definitions available

Support the unit of analysis chosen for exposure measurement (e.g., person-months of exposure) and discuss the trade-offs for alternative units of measurement

 

Address issues of differential and nondifferential bias related to exposure measurement and propose strategies for reducing error and bias, where possible