Correction notice

Michael V. Holmes, Seamus Harrison, Philippa J. Talmud, Aroon D. Hingorani & Steve E. Humphries. Utility of genetic determinants of lipids and cardiovascular events in assessing risk. Nat. Rev. Cardiol. 8, 207-221 (2011)

The version of the Supplementary Information originally posted online was the unedited version. The copy-edited version contain, which contains definitions of abbreviations used, replaced the originally posted file on 6 April 2011.


Supplementary Information

To generate the figures shown in Table 7 of the main article we used the following methodology.

Common Variants

Each hypothetical single nucleotide polymorphism (SNP) was assumed to have a risk allele frequency of 0.3 and a relative risk (RR) of 1.3 compared to a non-carrier. For simplicity, individuals were considered to be carriers or noncarriers. Each SNP was considered to have an independent and additive effect, such that carriage of each additional SNP increased the risk of cardiovascular disease (CVD) by 30%.

The relative risk (RR) of each SNP compared to the general population (RRpop ) is given by:

RRpop = (RAF *OR)+(1*NRAF)

Where OR = odds ratio for that SNP (compared with somebody without the SNP)

RAF = risk-allele frequency, and

NRAF = non-risk-allele frequency.

The distribution of 10 such risk alleles in the population is a binomial distribution (n=10, P=0.3). The distribution and risks associated with each combination of SNPs is shown in Supplementary Table 1.

No. of alleles / Relative risk compared to 0 alleles / Relative risk compared to average / Prevalence
0 / 1 / 0.53 / 0.0282
1 / 1.3 / 0.68 / 0.1211
2 / 1.6 / 0.84 / 0.2335
3 / 1.9 / 1.00 / 0.2668
4 / 2.2 / 1.16 / 0.2001
5 / 2.5 / 1.32 / 0.1029
6 / 2.8 / 1.47 / 0.0368
7 / 3.1 / 1.63 / 0.009
8 / 3.4 / 1.79 / 0.0014
9 / 3.7 / 1.95 / 0.0001
10 / 4 / 2.11 / 0.00001

Supplementary Table 1 – Risks for each genotype combination and relative frequencies in the population.

To calculate a mean RR for carriers of 4 or more alleles, or 3 or fewer alleles, a mean of the RR for each number of alleles was calculated, weighted for the relative frequency in the population.

Rare Variants

Each rare variant was assumed to have a frequency of 0.2% in the population, with double the risk of CVD compared with a noncarrier. The probability of carrying at least one of these variants is calculated from the binomial distribution, with n=180 and P=0.002.

Number needed to treat/screen (NNT/NNS) calculations

To calculate the NNS, we assumed a model of screening whereby everybody carrying a certain number of variants was treated with risk-factor modification and statins, with an assumed relative-risk reduction of 0.25. Absolute-risk figures were calculated by multiplying RR (per number of alleles carried) by lifetime risk of CHD (we used 40% in this case). The NNT is the inverse of the absolute risk reduction and the NNS is the NNT/prevalence of the genetic risk factor in the population studied.