Extended Data Fig. 2: Further analysis of influence of characteristics of genetic associations on relative success.
From: Refining the impact of genetic evidence on clinical success
A) Sensitivity of RS to the similarity threshold between the MeSH ID for the genetically associated trait and the MeSH ID for the clinically developed indication. The threshold is varied by units of 0.05 (labels) and the results are plotted as RS (y axis) versus number of genetically supported T-I pairs (x axis). B) Breakdown of OTG and OMIM RS values by whether any drug for each T-I pair has had orphan status assigned. The N of genetically supported T-I pairs (denominator) and, of those, launched T-I pairs (numerator) is shown at right. Values for the full 2×2 contingency table including the non-supported pairs, used to calculate RS, are provided in Table S12. Total N = 13,022 T-I pairs, of which 3,149 are orphan. The center is the RS point estimate and error bars are Katz 95% confidence intervals. C) RS for somatic genetic evidence from IntOGen versus germline genetic evidence, for oncology and non-oncology indications. Note that the approved/supported proportions displayed for the top two rows are identical because all IntOGen genetic support is for oncology indications, yet the RS is different because the number of non-supported approved and non-supported clinical stage programs is different. In other words, in the “All indications” row, there is a Simpson’s paradox that diminishes the apparent RS of IntOGen — IntOGen support improves success rate (see 2nd row) but also selects for oncology, an area with low baseline success rate (as shown in Extended Data Fig. 6a). N is displayed at right as in (B), with full contingency tables in Table S13. Total N = 13,022 T-I pairs, of which 6,842 non-oncology, 6,180 oncology, 1,287 targeting IntOGen oncogenes, 284 targeting tumor suppressors, and 176 targeting IntOGen genes of unknown mechanism. The center is the RS point estimate and error bars are Katz 95% confidence intervals. D) As for top panel of Fig. 1d, but without removing replications or OMIM-supported T-I pairs. N is displayed as in (B), with full contingency tables in Table S14. Total N = 13,022 T-I pairs. The center is the RS point estimate and error bars are Katz 95% confidence intervals. E) As for top panel of Fig. 1d, removing replications but not removing OMIM-supported T-I pairs. N is displayed as in (B), with full contingency tables in Table S15. Total N = 13,022 T-I pairs. The center is the RS point estimate and error bars are Katz 95% confidence intervals. F) Proportion of T-I pairs supported by a GWAS Catalog association that are launched (versus phase I-III) as a function of the year of first genetic association. G) Launched T-I pairs genetically supported by OTG GWAS, shown by year of launch (y axis) and year of first genetic association (x axis). Gene symbols are labeled for first approvals of targets with at least 5 years between association and launch. Of 104 OTG-supported launched T-I pairs (Fig. 1d), year of drug launch was available for N = 38 shown here, of which 18 (47%) acquired genetic support only in or after the year of launch. The true proportion of launched T-I whose GWAS support is retrospective may be larger if the T-I with a missing launch year are more often older drug approvals less well annotated in Pharmaprojects. H) Lack of impact of GWAS Catalog lead SNP odds ratio (OR) on RS when using the same OR breaks as used by King et al.15. N is displayed as in (B), with full contingency tables in Table S18. Total N = 13,022 T-I pairs. The center is the RS point estimate and error bars are Katz 95% confidence intervals. See Fig. S4 for the same analyses restricted to drugs with a single known target.