Randomised by (your) god: robust inference from an observational study design

Smith, George Davey

doi:10.1136/jech.2004.031880

Cited by 35 publications

(40 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…there are no confounding factors relating genotype to CHD and genotype is not related to CHD through other pathways) [8], [9], [10]. The rs1130864 SNP has been consistently shown to be associated with circulating CRP levels in males and females of European origin,[12], [20], [29]–[31] a finding that we have replicated here.…”

Section: Discussionsupporting

confidence: 77%

The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants

et al. 2008

View full text Add to dashboard Cite

BackgroundIt is unclear whether C-reactive protein (CRP) is causally related to coronary heart disease (CHD). Genetic variants that are known to be associated with CRP levels can be used to provide causal inference of the effect of CRP on CHD. Our objective was to examine the association between CRP genetic variant +1444C>T (rs1130864) and CHD risk in the largest study to date of this association.Methods and ResultsWe estimated the association of CRP genetic variant +1444C>T (rs1130864) with CRP levels and with CHD in five studies and then pooled these analyses (N = 18,637 participants amongst whom there were 4,610 cases). CRP was associated with potential confounding factors (socioeconomic position, physical activity, smoking and body mass) whereas genotype (rs1130864) was not associated with these confounders. The pooled odds ratio of CHD per doubling of circulating CRP level after adjustment for age and sex was 1.13 (95%CI: 1.06, 1.21), and after further adjustment for confounding factors it was 1.07 (95%CI: 1.02, 1.13). Genotype (rs1130864) was associated with circulating CRP; the pooled ratio of geometric means of CRP level among individuals with the TT genotype compared to those with the CT/CC genotype was 1.21 (95%CI: 1.15, 1.28) and the pooled ratio of geometric means of CRP level per additional T allele was 1.14 (95%CI: 1.11, 1.18), with no strong evidence in either analyses of between study heterogeneity (I2 = 0%, p>0.9 for both analyses). There was no association of genotype (rs1130864) with CHD: pooled odds ratio 1.01 (95%CI: 0.88, 1.16) comparing individuals with TT genotype to those with CT/CC genotype and 0.96 (95%CI: 0.90, 1.03) per additional T allele (I2<7.5%, p>0.6 for both meta-analyses). An instrumental variables analysis (in which the proportion of CRP levels explained by rs1130864 was related to CHD) suggested that circulating CRP was not associated with CHD: the odds ratio for a doubling of CRP level was 1.04 (95%CI: 0.61, 1.80).ConclusionsWe found no association of a genetic variant, which is known to be related to CRP levels, (rs1130864) and having CHD. These findings do not support a causal association between circulating CRP and CHD risk, but very large, extended, genetic association studies would be required to rule this out.

show abstract

Section: Discussionsupporting

confidence: 77%

The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Common genetic polymorphisms that have a well-characterized biological function (or are markers for such variants) can therefore be utilized to study the eVect of a suspected environmental exposure on disease risk (Davey Smith 2006;Davey Smith and Ebrahim 2003.…”

Section: Mendelian Randomizationmentioning

confidence: 99%

Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology?

2007

View full text Add to dashboard Cite

Establishing causal relationships between environmental exposures and common diseases is beset with problems of unresolved confounding, reverse causation and selection bias that may result in spurious inferences. Mendelian randomization, in which a functional genetic variant acts as a proxy for an environmental exposure, provides a means of overcoming these problems as the inheritance of genetic variants is independent of-that is randomized with respect to-the inheritance of other traits, according to Mendel's law of independent assortment. Examples drawn from exposures and outcomes as diverse as milk and osteoporosis, alcohol and coronary heart disease, sheep dip and farm workers' compensation neurosis, folate and neural tube defects are used to illustrate the applications of Mendelian randomization approaches in assessing potential environmental causes of disease. As with all genetic epidemiology studies there are problems associated with the need for large sample sizes, the non-replication of findings, and the lack of relevant functional genetic variants. In addition to these problems, Mendelian randomization findings may be confounded by other genetic variants in linkage disequilibrium with the variant under study, or by population stratification. Furthermore, pleiotropy of effect of a genetic variant may result in null associations, as may canalisation of genetic effects. If correctly conducted and carefully interpreted, Mendelian randomization studies can provide useful evidence to support or reject causal hypotheses linking environmental exposures to common diseases.

show abstract

“…16 Mendelian randomization has been proposed as a method akin to an RCT. 17,18 Within a given population, the inheritance of a particular allele at a given locus is independent of all other alleles at other loci except for those that are in LD with it, as described by Gregor Mendel in what was later to be referred to as his law of independent assortment, which states that traits are transmitted to offspring independently of one another. 19 However, the important feature of genotypes with respect to epidemiology is that the inheritance of alleles is assigned at conception and generally not associated with lifestyle factors that may confound an observational study.…”

Section: Why Not Just Carry Out An Rct?mentioning

confidence: 99%

Mendelian Randomization as Applied to Coronary Heart Disease, Including Recent Advances Incorporating New Technology

Lewis¹

2010

Circ Cardiovasc Genet

View full text Add to dashboard Cite

Randomised by (your) god: robust inference from an observational study design

Cited by 35 publications

References 55 publications

The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants

The Association of C-Reactive Protein and CRP Genotype with Coronary Heart Disease: Findings from Five Studies with 4,610 Cases amongst 18,637 Participants

Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology?

Mendelian Randomization as Applied to Coronary Heart Disease, Including Recent Advances Incorporating New Technology

Contact Info

Product

Resources

About