Limits...
Challenges and novel approaches for investigating molecular mediation

View Article: PubMed Central - PubMed

ABSTRACT

Understanding mediation is useful for identifying intermediates lying between an exposure and an outcome which, when intervened upon, will block (some or all of) the causal pathway between the exposure and outcome. Mediation approaches used in conventional epidemiology have been adapted to understanding the role of molecular intermediates in situations of high-dimensional omics data with varying degrees of success. In particular, the limitations of observational epidemiological study including confounding, reverse causation and measurement error can afflict conventional mediation approaches and may lead to incorrect conclusions regarding causal effects. Solutions to analysing mediation which overcome these problems include the use of instrumental variable methods such as Mendelian randomization, which may be applied to evaluate causality in increasingly complex networks of omics data.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of two-step Mendelian randomization In Step 1, a genetic variant, G1, is used to proxy for the environmentally-modifiable exposure of interest, E, to examine how this exposure influences in the intermediate, M, e.g. DNA methylation. In Step 2, a different genetic variant unrelated to the exposure, G2 is used to proxy for this specific difference in the intermediate, M, and relate this to the outcome of interest, Y.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5036871&req=5

ddw197-F5: Schematic diagram of two-step Mendelian randomization In Step 1, a genetic variant, G1, is used to proxy for the environmentally-modifiable exposure of interest, E, to examine how this exposure influences in the intermediate, M, e.g. DNA methylation. In Step 2, a different genetic variant unrelated to the exposure, G2 is used to proxy for this specific difference in the intermediate, M, and relate this to the outcome of interest, Y.

Mentions: In situations such as that outlined with respect to evaluating the role of a molecular intermediate (e.g. DNA methylation) in a known exposure-outcome relationship (e.g. smoking-lung cancer), it may be possible to obtain causal estimates from MR studies for all steps in the chain, e.g. from smoking to DNA methylation, and from DNA methylation to lung cancer, in a two-step Mendelian randomization approach (Fig. 5). Here the logic of MR can be extended to interrogate causality of a mediating effect using one genetic instrument to estimate the causal effect of the exposure on DNA methylation, and a separate independent instrument to estimate the causal effect of DNA methylation on the outcome. As variation in DNA methylation is associated with widespread local (cis) genetic variation, this provides the opportunity to use genetic proxies to probe causality between DNA methylation and particular outcomes using MR (5,42–44).Figure 5.


Challenges and novel approaches for investigating molecular mediation
Schematic diagram of two-step Mendelian randomization In Step 1, a genetic variant, G1, is used to proxy for the environmentally-modifiable exposure of interest, E, to examine how this exposure influences in the intermediate, M, e.g. DNA methylation. In Step 2, a different genetic variant unrelated to the exposure, G2 is used to proxy for this specific difference in the intermediate, M, and relate this to the outcome of interest, Y.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036871&req=5

ddw197-F5: Schematic diagram of two-step Mendelian randomization In Step 1, a genetic variant, G1, is used to proxy for the environmentally-modifiable exposure of interest, E, to examine how this exposure influences in the intermediate, M, e.g. DNA methylation. In Step 2, a different genetic variant unrelated to the exposure, G2 is used to proxy for this specific difference in the intermediate, M, and relate this to the outcome of interest, Y.
Mentions: In situations such as that outlined with respect to evaluating the role of a molecular intermediate (e.g. DNA methylation) in a known exposure-outcome relationship (e.g. smoking-lung cancer), it may be possible to obtain causal estimates from MR studies for all steps in the chain, e.g. from smoking to DNA methylation, and from DNA methylation to lung cancer, in a two-step Mendelian randomization approach (Fig. 5). Here the logic of MR can be extended to interrogate causality of a mediating effect using one genetic instrument to estimate the causal effect of the exposure on DNA methylation, and a separate independent instrument to estimate the causal effect of DNA methylation on the outcome. As variation in DNA methylation is associated with widespread local (cis) genetic variation, this provides the opportunity to use genetic proxies to probe causality between DNA methylation and particular outcomes using MR (5,42–44).Figure 5.

View Article: PubMed Central - PubMed

ABSTRACT

Understanding mediation is useful for identifying intermediates lying between an exposure and an outcome which, when intervened upon, will block (some or all of) the causal pathway between the exposure and outcome. Mediation approaches used in conventional epidemiology have been adapted to understanding the role of molecular intermediates in situations of high-dimensional omics data with varying degrees of success. In particular, the limitations of observational epidemiological study including confounding, reverse causation and measurement error can afflict conventional mediation approaches and may lead to incorrect conclusions regarding causal effects. Solutions to analysing mediation which overcome these problems include the use of instrumental variable methods such as Mendelian randomization, which may be applied to evaluate causality in increasingly complex networks of omics data.

No MeSH data available.


Related in: MedlinePlus