Assessment of cumulative evidence on genetic associations: interim guidelines

Abstract

Established guidelines for causal inference in epidemiological studies may be inappropriate for genetic associations. A consensus process was used to develop guidance criteria for assessing cumulative epidemiologic evidence in genetic associations. A proposed semi-quantitative index assigns three levels for the amount of evidence, extent of replication, and protection from bias, and also generates a composite assessment of 'strong', 'moderate' or 'weak' epidemiological credibility. In addition, we discuss how additional input and guidance can be derived from biological data. Future empirical research and consensus development are needed to develop an integrated model for combining epidemiological and biological evidence in the rapidly evolving field of investigation of genetic factors.

Investigation of DNA polymorphisms in SMAD genes for genetic predisposition to diabetic nephropathy in patients with type 1 diabetes mellitus

“…The lack of replication may be due to different patterns of LD (and hence different tag SNPs) across different populations [13]; however, this is unlikely as HapMap tag SNPs have been shown to be transferable across European ancestry [14]. The lack of independent replication may be due to epistasis [13], but it is most likely that the original finding was a false positive association highlighted by chance as a result of a lower MAF in a smaller sample size.…”

“…The lack of independent replication may be due to epistasis [13], but it is most likely that the original finding was a false positive association highlighted by chance as a result of a lower MAF in a smaller sample size. The sample size of the initial Irish collection provided 90% power to detect an OR equal to 1.75 with a MAF of 10%.…”

Use of genomic panels to determine risk of developing type 2 diabetes in the general population: a targeted evidence-based review

“…21 These "Venice criteria" focused on amount of evidence, replication of evidence, and protection from bias. Each criterion is assigned a grade of "A, " "B, " or "C. " The amount of evidence, for example, would receive an "A" if >1,000 cases/controls with the least common genotype were included in computing the effect size estimate, "B" if there were 100-1,000 study subjects, and "C" if <100.…”

“…Each criterion is assigned a grade of "A, " "B, " or "C. " The amount of evidence, for example, would receive an "A" if >1,000 cases/controls with the least common genotype were included in computing the effect size estimate, "B" if there were 100-1,000 study subjects, and "C" if <100. As suggested in this grading system, 21 epidemiological evidence for a significant association was rated as "strong" if the meta-analysis received three A grades, "moderate" if it received any B grade but not any C grade, and "weak" if it received a C grade in any of the three criteria. These criteria may not be as relevant for assessing evidence from large GWA studies.…”

“…Additional genes not included in commercially available tests were included when results from GWA studies meta-analysis or original GWA studies were available. A table listing all of the 21 that use three letter grades (A, B, and C) to determine credibility of a meta-analysis. Amount of evidence: A = over 1,000 cases and controls in least common genotype (assuming 1:1), B = 100-1000, C = <100.…”