Negative Control Exposures in Epidemiologic Studies
Abstract
To the Editor: In their excellent review on negative controls,1 Lipsitch and colleagues1 state they “are not aware of an example of the use of a negative control exposure to detect confounding” in an epidemiologic setting. One such explicit application of this approach relates to the use of paternal exposures as a negative control exposure for maternal exposures considered to have an intrauterine influence on offspring outcomes.2 Paternal smoking, as a negative control, may show associations with offspring outcomes similar to those of maternal smoking if the associations are generated by shared familial confounding factors or by parental genotypes transmitted to the offspring. If, however, there is an intrauterine influence, then only the maternal exposure would be expected to show an independent association with the outcome. Figure 1 demonstrates that the effect of maternal smoking during pregnancy on offspring birthweight is considerably greater than that of paternal smoking during pregnancy, and mutual adjustment (to take account of associative mating by smoking) attenuates the paternal effect to zero. This is in line with the considerable body of evidence that maternal smoking has a causal effect on offspring birthweight. There has been enthusiasm for the proposition that fetal exposure to maternal smoking leads to increased obesity in offspring.3 Although maternal smoking during pregnancy does indeed demonstrate the expected association, the strength of association with paternal smoking during pregnancy is similar before and after mutual adjustment (Fig. 2).4 This casts doubt on the causal nature of the association between intrauterine exposure to maternal smoking and offspring adiposity.Figure 1: Effect of maternal and paternal smoking on offspring birthweight (difference in birthweight between offspring of smokers and nonsmokers in grams).Figure 2: Effect of maternal and paternal smoking during pregnancy on offspring body mass index (difference in body mass index between offspring of smokers and nonsmokers in kg/m2).As Lipsitch and colleagues1 argue, the use of negative controls could be usefully expanded in epidemiology. If associations are found with such controls, this does not invalidate the observation under interrogation but does encourage further intense scrutiny of potential biases and confounding that may underlie what is seen. George Davey Smith MRC Centre for Causal Analyses in Translational Epidemiology University of Bristol Bristol, United Kingdom [email protected]
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In negative control studies, an unbiased negative control study is expected to be null and the real study not-null if there is a true causal effect and the assumptions of the approach are met.
“In a third approach–negative control studies–we would expect an unbiased negative control study to be null and the ‘real’ study not-null if there is a true causal effect and the assumptions of this approach are met (see Table 1).39,40”
From Triangulation in aetiological epidemiology (2017) · cites this paper as [40]
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“The largest source of second-hand smoking among non-smoking pregnant women being partner’s smoking [ 56 ], paternal smoking in pregnancy does not match the ideal negative control configuration [ 57 ].”
Øyri, L. K. L., Christensen, J. J., Sebert, S., Thoresen, M., Michelsen, T. M., Ulven, S. M., Brekke, H. K., Retterstøl, K., Brantsæter, A. L., Magnus, P. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22610717
Øyri, L. K. L., Christensen, J. J., Sebert, S., Thoresen, M., Michelsen, T. M., Ulven, S. M., Brekke, H. K., Retterstøl, K., Brantsæter, A. L., Magnus, P. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22610708
Taylor, K., Wootton, R. E., Yang, Q., Oddie, S., Wright, J., Yang, T. C., Magnus, M., Andreassen, O. A., Borges, M. C., Caputo, M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22610789
Øyri, L. K. L., Christensen, J. J., Sebert, S., Thoresen, M., Michelsen, T. M., Ulven, S. M., Brekke, H. K., Retterstøl, K., Brantsæter, A. L., Magnus, P. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22610711
Øyri, L. K. L., Christensen, J. J., Sebert, S., Thoresen, M., Michelsen, T. M., Ulven, S. M., Brekke, H. K., Retterstøl, K., Brantsæter, A. L., Magnus, P. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22610705
Øyri, L. K. L., Christensen, J. J., Sebert, S., Thoresen, M., Michelsen, T. M., Ulven, S. M., Brekke, H. K., Retterstøl, K., Brantsæter, A. L., Magnus, P. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22610723
Taylor, K., Wootton, R. E., Yang, Q., Oddie, S., Wright, J., Yang, T. C., Magnus, M., Andreassen, O. A., Borges, M. C., Caputo, M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22610792
Øyri, L. K. L., Christensen, J. J., Sebert, S., Thoresen, M., Michelsen, T. M., Ulven, S. M., Brekke, H. K., Retterstøl, K., Brantsæter, A. L., Magnus, P. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22610702
Øyri, L. K. L., Christensen, J. J., Sebert, S., Thoresen, M., Michelsen, T. M., Ulven, S. M., Brekke, H. K., Retterstøl, K., Brantsæter, A. L., Magnus, P. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22610714
Øyri, L. K. L., Christensen, J. J., Sebert, S., Thoresen, M., Michelsen, T. M., Ulven, S. M., Brekke, H. K., Retterstøl, K., Brantsæter, A. L., Magnus, P. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22610720
Øyri, L. K. L., Christensen, J. J., Sebert, S., Thoresen, M., Michelsen, T. M., Ulven, S. M., Brekke, H. K., Retterstøl, K., Brantsæter, A. L., Magnus, P. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.22610699
Using Negative Control Outcomes to Detect Selection Bias in Mendelian Randomization Studies
Gkatzionis, A., Smith, G. D., & Tilling, K. M. (2026) · Statistics in Medicine · doi:10.1002/sim.70703
Self-citationBoyle, T., Boing, L., Jefferis, B. J. M. H., Alkahtani, S. A., Bennett, D., Kontostoli, E., McLaughlin, M. J., Oluwayomi, A., Sadarangani, K. P., Rosen, P., et al. (2026) · Journal of Physical Activity and Health · doi:10.1123/jpah.2025-0744
- Authors
- Smith, G. D.
- Affiliations
- University of Bristol (GB)
- Corresponding author
- Smith, George Davey
- ORCID
- Smith, George Davey
- Venue
- Epidemiology
- Published
- 2012-03
- Volume
- 23
- Issue
- 2
- Pages
- 350-351
- ISSN
- 1044-3983 (ISSN-L)
- OpenAlex
- W2026534761
- Cited by
- 88
- References
- 4
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 5 · 2023: 19 · 2022: 5 · 2021: 5 · 2020: 9 · 2019: 7 · 2018: 2 · 2017: 7 · 2016: 5 · 2015: 2 · 2014: 6 · 2013: 6 · 2012: 1
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Epidemiology (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Topics
- Physical Sciences › Mathematics › Statistics and Probability › Advanced Causal Inference Techniques
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- paternal smoking, maternal smoking, prenatal exposure, offspring adiposity, mutual adaptation, causal inference, body mass index
- MeSH terms
- Humans, Bias, Confounding Factors, Epidemiologic, Observation
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