Calculations

The economic burden was estimated by:

estimated economic burden per drug (£) = NHS cost per drug per year (£) x

% individuals with a MV in a functional site of the respective drug targets

where:

• The average NHS cost is the average yearly cost over a 4-year period (2013-2016) per GPCR drug that is listed (2012 and 2017 have uncomplete sales data).
• % Individuals is the percentage of affected individuals with a missense variant in a functional site of the respective drug target(s) (2,504 individuals from 1,000 Genomes Project Phase 3 genotype data)
• The fraction of affected individuals was calculated using two different criteria (a) considering only individuals who have a variation in a functional site in both alleles (homozygous), which is more conservative and (b) individuals if they have a variation in a functional site in at least one allele (i.e. homozygous and heterozygous), which is less conservative.
• Functional sites were distinguished into (a) known functional sites that included ligand binding, effector binding, PTM site, sodium binding site and microswitches (more conservative) and (b) putative functional site as those predicted to be deleterious based on SIFT or PolyPhen (less conservative).

More specifically, for each drug we collected the respective targets and computed economic burden using the following four categories: i) individuals with homozygous alleles in known functional sites ii) individuals with at least one variant allele in a known functional site, iii) individuals with homozygous alleles in known or putative functional sites iv) individuals with at least one variant allele in a known or putative functional sites. For these estimates, we consider that each prescription (NHS data) is made for a unique individual, due to patient anonymity.

Sales and variation information per drug