Extended Data Fig. 2: Estimation of true FDR using age distributions of individuals with mCA calls.

We generated age distributions for (i) ‘high-confidence’ detected events passing a permutation-based FDR threshold of 0.01 (bright red); (ii) ‘medium-confidence’ events below the FDR threshold of 0.01 but passing an FDR threshold of 0.05 (darker red); and (iii) ‘low-confidence’ events below the FDR threshold of 0.05 but passing an FDR threshold of 0.10 (darkest red; not analysed but plotted for context). We compared these distributions to the overall age distribution of UK Biobank participants (grey). On the basis of the numbers of events in each category, approximately 20% of medium-confidence detected events are expected to be false positives. To estimate our true FDR, we regressed the medium-confidence age distribution on the high-confidence and overall age distributions, reasoning that the medium-confidence age distribution should be a mixture of correctly called events with age distribution similar to that of the high-confidence events, and spurious calls with age distribution similar to the overall cohort. We observed a regression weight of 0.31 for the component corresponding to spurious calls, in good agreement with expectation, and implying a true FDR of 7.5% (6.2–8.8%, 95% CI based on regression fit on n = 6 age bins).