Survival Bias in Mendelian Randomization Studies: A Threat to Causal Inference - PubMed (original) (raw)

Survival Bias in Mendelian Randomization Studies: A Threat to Causal Inference

Roelof A J Smit et al. Epidemiology. 2019 Nov.

Abstract

It has been argued that survival bias may distort results in Mendelian randomization studies in older populations. Through simulations of a simple causal structure we investigate the degree to which instrumental variable (IV)-estimators may become biased in the context of exposures that affect survival. We observed that selecting on survival decreased instrument strength and, for exposures with directionally concordant effects on survival (and outcome), introduced downward bias of the IV-estimator when the exposures reduced the probability of survival till study inclusion. Higher ages at study inclusion generally increased this bias, particularly when the true causal effect was not equal to null. Moreover, the bias in the estimated exposure-outcome relation depended on whether the estimation was conducted in the one- or two-sample setting. Finally, we briefly discuss which statistical approaches might help to alleviate this and other types of selection bias. See video abstract at, http://links.lww.com/EDE/B589.

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Conflict of interest statement

The authors report no conflicts of interest.

Figures

FIGURE 1.

FIGURE 1.

For two exposures increasing the risk of death, conditioning on survival (S) may induce an association between the previously uncorrelated risk factors X (and its genetic proxy G) and R (panel A). Additionally, conditioning on survival may induce an association between the genetic instrument G and any confounders U of the X–Y association (panel B), even in the absence of risk factor R.

FIGURE 2.

FIGURE 2.

Estimating the causal effect of X on Y. Wald ratios (95% CI) based on internally (white ribbon) versus externally (gray ribbon) estimated X–Y association, for different true effects of exposure X on outcome Y. Dashed lines denote the true (i.e., unselected) Wald ratio, which equals the true causal effect of X on Y. CI, confidence interval.

References

    1. Boef AG, le Cessie S, Dekkers OM. Mendelian randomization studies in the elderly. Epidemiology. 2015;26:e15–e16. - PubMed
    1. Canan C, Lesko C, Lau B. Instrumental variable analyses and selection bias. Epidemiology. 2017;28:396–398. - PMC - PubMed
    1. Hernán MA, Hernández-Díaz S, Robins JM. A structural approach to selection bias. Epidemiology. 2004;15:615–625. - PubMed
    1. University of California, Berkeley (USA), and Max Planck Institute for Demographic Research (Germany). Human Mortality Database. Available at: www.mortality.org or www.humanmortality.de. Accessed July 30 2018.
    1. Burgess S, Butterworth A, Thompson SG. Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol. 2013;37:658–665. - PMC - PubMed

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