Biosocial Surveys (2008) / Chapter Skim
Currently Skimming:
16 Mendelian Randomization: Genetic Variants as Instruments for Strengthening Causal Inference in Observational Studies--George Davey Smith and Shah Ebrahim
16 Mendelian Randomization: Genetic Variants as Instruments for Strengthening Causal Inference in Observational Studies--George Davey Smith and Shah Ebrahim
Pages 336-366
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 336... ...
This chapter briefly outlines when and why conventional observational approaches have been misleading and then introduces the Mendelian randomization approach, a form of the use of genes as instrumental variables as briefly discussed by Douglas Ewbank in the earlier Cells and Surveys volume (Ewbank, 2001)
|
From page 337... ...
The impetus for thinking of new approaches is that conventional observational study designs have yielded findings that have failed to be confirmed by randomized controlled trials (Davey Smith and Ebrahim, 2002)
|
From page 338... ...
Importantly, the trial findings cannot be attributed to confounding or self-selection of healthier people into a vitamintaking group, as taking or not taking vitamin E was determined randomly, which (providing it is done properly) avoids these sources of bias.
|
From page 339... ...
. NOTE: Observed effect of duration of vitamin E use compared with no use on coronary heart disease events in the Health Professional Follow-up Study.
|
From page 340... ...
A century ago, Charles Spearman demonstrated mathematically how such measurement imprecision would lead to what he termed the "attenuation by errors" of associations (Spearman, 1904; Davey Smith and Phillips, 1996) , later renamed "regression dilution bias." Observational studies can and do produce findings that either spuriously enhance or downgrade estimates of causal associations between modifiable exposures and disease.
|
From page 341... ...
First, unlike environmental exposures, genetic variants are not generally associated with the wide range of behavioral, social, or physiological factors that, for example, confound the association between vitamin C and coronary heart disease. This means that if a genetic variant is used to proxy for an environmentally modifiable exposure, it is unlikely to be confounded in the way that direct measures of the exposure will be.
|
From page 342... ...
22.2 19.6 18.8 14.0 < 0.001 SOURCE: Davey Smith et al.
|
From page 343... ...
CRP = C-reactive protein. SOURCE: Davey Smith et al.
|
From page 344... ...
; here illustrative cases of the first two categories are briefly outlined. Exposure Propensity: Alcohol Intake and Health The possible protective effect of moderate alcohol consumption on risk of coronary heart disease (CHD)
|
From page 345... ...
. As well as this form of reverse causation, confounding could play a role, with nondrinkers being more likely to display an adverse profile of socioeconomic or other behavioral risk factors for coronary heart disease (Hart, Davey Smith, Hole, and Hawthorne, 1999)
|
From page 346... ...
Statistical adjustment for HDL cholesterol greatly attenuated the association between ALDH2 genotype and coronary heart disease, indicating that the cardio-protective effect of alcohol is mediated by increased levels of HDL cholesterol. Age 70 Smoker 70 60 Percentage 60 50 Years 40 50 30 40 20 2*
|
From page 347... ...
Proof of principle for this approach is provided by familial hypercholesterolemia genetic variants that are associated with higher circulating cholesterol levels, which increase risk of coronary heart disease. These observational data are in line with the randomized controlled trial evidence confirming that lowering cholesterol reduces the risk of coronary heart disease (Davey Smith and Ebrahim, 2004)
|
From page 348... ...
associated with elevated cholesterol level and CHD risk strengthens causal evidence that elevated cholesterol is a modifiable risk factor for coronary heart disease for the whole population. Thus even though the population attributable risk for coronary heart disease of this variant is small, it usefully informs public health approaches to improving population health.
|
From page 349... ...
The analogy with randomized controlled trials is also useful in understanding why an objection to Mendelian randomization -- that the environmentally modifiable exposure proxied for by the genetic variants (such as alcohol intake or circulating CRP levels) are influenced by many other factors in addition to the genetic variants (Jousilahti and Salomaa, 2004)
|
From page 350... ...
Thus the fact that many other factors are related to the modifiable exposure does not vitiate the power of randomized controlled trials; neither does it vitiate the strength of Mendelian randomization designs. A related objection is that genetic variants often explain only a trivial proportion of the variance in the environmentally modifiable risk factor that is being proxied for (Glynn, 2006)
|
From page 351... ...
The development of instrumental variable methods in econometrics, in particular, has led to a sophisticated range of statistical methods for estimating causal effects, and these have now been applied in Mendelian randomization studies (e.g., Davey Smith et al., 2005a, 2005b; Timpson et al., 2005)
|
From page 352... ...
, resulting in a large number of reports of spurious gene-environment interactions in the medical literature (Colhoun, McKeigue, and Davey Smith, 2003)
|
From page 353... ...
When intermediate phenotypes can be measured, as in the case of CRP, a demonstration of the expected relationship between genotype and intermediate phenotype in such studies indicates that genotyping errors are not to blame. Regarding failure to replicate results in genetic epidemiology, true variation between studies is clearly possible -- for example, people heterozygous for familial hypercholesterolemia seem to experience increased mortality only in populations with substantial dietary fat intake and the presence of other CHD risk factors (Sijbrands et al., 2001; Pimstone et al.,
|
From page 354... ...
. Confounding of Genotype: Environmentally Modifiable Risk Factor–Disease Associations The power of Mendelian randomization lies in its ability to avoid the often substantial confounding seen in conventional observational epidemiology.
|
From page 355... ...
The association of possession of the ApoE-2 allele with cholesterol levels and coronary heart disease might be an example of pleiotropic effects, since carriers of this allele have lower cholesterol levels but do not have the degree of protection against coronary heart disease that would be anticipated from this (Keavney et al., 2004; Song, Stampfer, and Liu, 2004)
|
From page 356... ...
Empirical studies to date suggest that common genetic variants are largely unrelated to the behavioral and socioeconomic factors considered to be important confounders in conventional observational studies (Smits et al., 2004; Bhatti et al., 2005; Davey Smith et al., 2005b, 2007; Chatterjee, Kalaylioglu, and Carroll, 2005; Umbach and Weinberg, 1997)
|
From page 357... ...
Most examples of developmental compensation relate to dramatic genetic or environmental insults, so it is unclear whether the generally small phenotypic differences induced by common functional polymorphisms will be sufficient to induce compensatory responses. The fact that the large gene-environment interactions that have been observed often relate to novel exposures (e.g., drug interactions)
|
From page 358... ...
, of how observational epidemiology appeared to have got the wrong answer related to vitamin C, we considered whether the association between vitamin C and coronary heart disease could have been studied utilizing the principles of Mendelian randomization. We stated that polymorphisms exist that are related to lower circulating vitamin C levels -- for example, the haptoglobin polymorphism (Langlois, Delanghe, DeBuyzere, Bernard, and Ouyang, 1997; Delanghe, Langlois, Duprez, DuBuyzere, and Clement, 1999)
|
From page 359... ...
Mendelian Randomization and Genetic Epidemiology Critiques of contemporary genetic epidemiology often focus on two features of findings from genetic association studies: that the populationattributable risk of the genetic variants is low, and that in any case the influence of genetic factors is not reversible (Terwilliger and Weiss, 2003)
|
From page 360... ...
. However, by identifying blood cholesterol levels as a causal factor for coronary heart disease, the triangulation between genotype, blood cholesterol, and CHD risk identifies an environmentally modifiable factor with a very high population attributable risk -- assuming that 50 percent of the population have raised blood cholesterol above 6.0 mmol/l, and this is associated with a relative risk of two-fold, a population attributable risk of 33 percent is obtained.
|
From page 361... ...
. C-reactive protein and other circulat ing markers of inflammation in the prediction of coronary heart disease.
|
From page 362... ...
. Does el evated plasma fibrinogen increase the risk of coronary heart disease?
|
From page 363... ...
. Alcohol consumption and mortality from all causes, coronary heart disease, and stroke: Results from a prospec tive cohort study of Scottish men with 21 years of follow up.
|
From page 364... ...
. A prospective study of antioxidant vitamins and incidence of coronary heart disease in women.
|
From page 365... ...
. Commentary: Alcohol and coronary heart disease -- Laying the foundation for future work.
|
From page 366... ...
. Population stratification in epidemio logic studies of common genetic variants and cancer: Quantification of bias.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.