Sample size needed for power calculation

I am analyzing tumor DNA sequencing data to perform variant calling. I need to find the minimum number of DNA strands (sample size; independent samples, 'depth of coverage') needed to detect mutations occurring at frequencies of 2-5%, with 95% confidence, given a 1% background mutation rate, at power levels of 0.8, 0.9, and 0.99.

Past collaborators did this, using a "cloglog Binomial distribution"(?), and got some of the following results:

frequency: 0.02
power: 0.8
alpha: 0.05
sample size: 1239

frequency: 0.03
power: 0.8
alpha: 0.05
sample size: 423

frequency: 0.04
power: 0.90
alpha: 0.05
sample size: 299

frequency: 0.05
power: 0.99
alpha: 0.05
sample size: 315

I am trying to replicate their analysis in R, to validate and fill in more values, but it seems like I am doing something wrong because I am not getting the same values. Using the pwr library:

library("pwr")
pwr.p.test(h = 0.02,
sig.level = 0.05,
power = 0.80,
alternative = "greater")

output:

proportion power calculation for binomial distribution (arcsine transformation)

h = 0.02
n = 15456.39
sig.level = 0.05
power = 0.8
alternative = greater

Here, it is giving me an n of 15456, when the value should be 1239

As per the docs for this package, the 'effect size' is important, so I am wondering if that might be the source of the discrepancy? And I am not sure how the 'coglog Binomial distribution' plays into it, especially since pwr says it uses an 'arcsine transformation' instead.

• cloglog = "complementary log log" so that the probability is modeled linearly on this scale $\log(-\log(p)) = \beta_0 + \beta_1 X$. It is good for discrete time survival. There's a nice discussion on these types of models in Applied Survival Analysis by Hosmer, Lemeshow, and May 2nd ed or later. – AdamO Mar 5 '18 at 16:28

Found the solution, using the binom R package instead. For context:

• Null Hypothesis: No variant present, background error rate only (1%)

• Alternative Hypothesis: A variant is present at the given frequency (Variant Allele Frequency; 2%)

code:

library("binom")
VAF <- 0.02
background_seq_error_rate <- 0.01
alpha <- 0.05
conf_level <- 1 - alpha
power <- 0.8

cloglog.sample.size(p.alt = VAF,
p = background_seq_error_rate,
power = power,
alpha = alpha)

output:

p.null p.alt delta alpha power    n phi
1   0.01  0.02  0.01  0.05   0.8 1239   1

Software:

• R version 3.2.3 (2015-12-10)

• binom_1.1-1