Dataset Information

History of Benzodiazepine Prescriptions and Risk of Dementia: Possible Bias Due to Prevalent Users and Covariate Measurement Timing in a Nested Case-Control Study.

ABSTRACT: Previous estimates of whether long-term exposure to benzodiazepines increases dementia risk are conflicting and are compromised by the difficulty of controlling for confounders and by reverse causation. We investigated how estimates for the association between benzodiazepine use and later dementia incidence varied based on study design choices, using a case-control study nested within the United Kingdom's Clinical Practice Research Datalink. A total of 40,770 dementia cases diagnosed between April 2006 and July 2015 were matched on age, sex, available data history, and deprivation to 283,933 control subjects. Benzodiazepines and Z-drug prescriptions were ascertained in a drug-exposure period 4-20 years before dementia diagnosis. Estimates varied with the inclusion of new or prevalent users, with the timing of covariate ascertainment, and with varying time between exposure and outcome. There was no association between any new prescription of benzodiazepines and dementia (adjusted odds ratio (OR) = 1.03, 95% confidence interval (CI): 1.00, 1.07), whereas an inverse association was observed among prevalent users (adjusted OR = 0.91, 95% CI: 0.87, 0.95), although this was likely induced by unintentional adjustment for colliders. By considering the choice of confounders and timing of exposure and covariate measurement, our findings overall are consistent with no causal effect of benzodiazepines or Z-drugs on dementia incidence.

SUBMITTER: Richardson K

PROVIDER: S-EPMC6601519 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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History of Benzodiazepine Prescriptions and Risk of Dementia: Possible Bias Due to Prevalent Users and Covariate Measurement Timing in a Nested Case-Control Study.

Richardson Kathryn K Mattishent Katharina K Loke Yoon K YK Steel Nicholas N Fox Chris C Grossi Carlota M CM Bennett Kathleen K Maidment Ian I Boustani Malaz M Matthews Fiona E FE Myint Phyo K PK Campbell Noll L NL Brayne Carol C Robinson Louise L Savva George M GM

American journal of epidemiology 20190701 7

Previous estimates of whether long-term exposure to benzodiazepines increases dementia risk are conflicting and are compromised by the difficulty of controlling for confounders and by reverse causation. We investigated how estimates for the association between benzodiazepine use and later dementia incidence varied based on study design choices, using a case-control study nested within the United Kingdom's Clinical Practice Research Datalink. A total of 40,770 dementia cases diagnosed between Apr ...[more]

PMID: 31111865

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Project description:PurposeIn studies of effects of time-varying drug exposures, adequate adjustment for time-varying covariates is often necessary to properly control for confounding. However, the granularity of the available covariate data may not be sufficiently fine, for example when covariates are measured for participants only when their exposure levels change.MethodsTo illustrate the impact of choices regarding the frequency of measuring time-varying covariates, we simulated data for a large target trial and for large observational studies, varying in covariate measurement design. Covariates were measured never, on a fixed-interval basis, or each time the exposure level switched. For the analysis, it was assumed that covariates remain constant in periods of no measurement. Cumulative survival probabilities for continuous exposure and non-exposure were estimated using inverse probability weighting to adjust for time-varying confounding, with special emphasis on the difference between 5-year event risks.ResultsWith monthly covariate measurements, estimates based on observational data coincided with trial-based estimates, with 5-year risk differences being zero. Without measurement of baseline or post-baseline covariates, this risk difference was estimated to be 49% based on the available observational data. With measurements on a fixed-interval basis only, 5-year risk differences deviated from the null, to 29% for 6-monthly measurements, and with magnitude increasing up to 35% as the interval length increased. Risk difference estimates diverged from the null to as low as -18% when covariates were measured depending on exposure level switching.ConclusionOur simulations highlight the need for careful consideration of time-varying covariates in designing studies on time-varying exposures. We caution against implementing designs with long intervals between measurements. The maximum length required will depend on the rates at which treatments and covariates change, with higher rates requiring shorter measurement intervals.

Dataset Information

History of Benzodiazepine Prescriptions and Risk of Dementia: Possible Bias Due to Prevalent Users and Covariate Measurement Timing in a Nested Case-Control Study.

Publications

History of Benzodiazepine Prescriptions and Risk of Dementia: Possible Bias Due to Prevalent Users and Covariate Measurement Timing in a Nested Case-Control Study.

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