Useful Info

Key functions

The two main functions are:

1. corrcov (or analogously corrcov_bhat): Provides a corrected coverage estimate of credible sets obtained using the Bayesian approach for fine-mapping (see “Corrected Coverage” vignette).

• Use corrcov for \(Z\)-scores and minor allele frequencies
• Use corrcov_bhat for beta hat estimates and their standard errors.

2. corrected_cs (or analogously corrected_cs_bhat): Finds a corrected credible set, which is the smallest set of variants such that the corrected coverage is above some user defined “desired coverage” (see "Corrected credible set vignette).

• Use corrected_cs for \(Z\)-scores and minor allele frequencies
• Use corrected_cs_bhat for beta hat estimates and their standard errors.

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Additional useful functions

• corrcov_nvar (or analogously corrcov_nvar_bhat): Finds a corrected coverage estimate whereby the simulated credible sets used to derive the estimate are limited to those which contain a specified number of variants (parameter ‘nvar’). These functions should be used with caution and only ever for very small credible sets (fewer than 4 variants).

• corrcov_CI (or analogously corrcov_CI_bhat): Finds a confidence interval for the corrected coverage estimate. The default is a 95% confidence interval (parameter CI = 0.95), but can be adjusted accordingly. This function involves repeating the correction procedure 100 times and therefore requires lots of memory.

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Conversion functions

The Bayesian method for fine-mapping involves finding the posterior probability of causality for each SNP, before sorting these into descending order and adding variants to a ‘credible set’ until the combined posterior probabilities of these SNPs exceed some threshold. The supplementary text of Maller’s paper (available here) shows that these posterior probabilities are normalised Bayes factors.

Asymptotic Bayes factors (Wakefield, 2009) are commonly used in genetic association studies as these only require the specification of \(Z\)-scores (or equivalently the effect size coefficients, \(\beta\), and their standard errors, \(V\)), the standard errors of the effect sizes (\(V\)) and the prior variance of the estimated effect size (\(W^2\)), thus only requiring summary data from genetic association studies plus an estimate for the \(W\) parameter.

Consequently, the corrcoverage package contains functions for converting between \(P\)-values, \(Z\)-scores, asymptotic Bayes factors (ABFs) and posterior probabilities of causality (PPs). The following table shows what input these conversion functions require and what output they produce. The ‘include null model’ column is for whether the null model of no genetic effect is included in the calculation (PPs obtained using the standard Bayesian approach ignore this).

Function	Include null model?	Input	Output
approx.bf.p	YES	\(P\)-values	log(ABF)
pvals_pp	YES	\(P\)-values	Posterior Probabilities
z0_pp	YES	Marginal \(Z\)-scores	Posterior Probabilities
ppfunc	NO	Marginal \(Z\)-scores	Posterior Probabilities

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Marginal and joint Z scores

Functions are also provided to simulate marginal \(Z\)-scores from joint \(Z\)-scores (\(Z_j\)). The joint \(Z\)-scores are all 0, except at the causal variant where it is the “true effect”, \(\mu\).

\(\mu\) can be estimated using the est_mu function which requires sample sizes, marginal \(Z\)-scores and minor allele frequencies. We estimate \(\mu\) by \[\hat\mu=\sum_{j}|Z_j|\times PP_j\]

The z_sim function simulates marginal \(Z\)-scores from joint \(Z\)-scores, whilst zj_pp can be used to simulate posterior probability systems from a joint \(Z\)-score vector. These functions first calculate the expected marginal \(Z\) scores, \(E(Z)\), \[E(Z)=Z_j \times \Sigma\] where \(\Sigma\) is the correlation matrix between SNPs.

We can then simulate more \(Z\)-score systems from a multivariate normal distribution with mean \(E(Z)\) and variance \(\Sigma\). This is a key step in our corrected coverage method.