## Saturday, 6 July 2019

### Correction: The harmonic mean p-value for combining dependent tests

Important: this announcement has been superceded. Please see updated correction

I would like to issue the following correction to users of the harmonic mean p-value (HMP), with apologies: The paper (Wilson 2019 PNAS 116: 1195-1200) erroneously states that the following asymptotically exact test controls the strong-sense family-wise error rate for any subset of p-values $$\mathcal{R}$$:
$$\overset{\circ}{p}_\mathcal{R} \leq \alpha_{|\mathcal{R}|}\,w_\mathcal{R}$$
$$\overset{\circ}{p}_\mathcal{R} \leq \alpha_{L}\,w_\mathcal{R}$$
where:
• L is the total number of individual p-values.
• $$\mathcal{R}$$ represents any subset of those p-values.
• $$\overset{\circ}{p}_\mathcal{R} = \left(\sum_{i\in\mathcal{R}} w_i\right)/\left(\sum_{i\in\mathcal{R}} w_i/p_i\right)$$ is the HMP for subset $$\mathcal{R}$$.
• $$w_i$$ is the weight for the ith p-value. The weights must sum to one: $$\sum_{i=1}^L w_i=1$$. For equal weights, $$w_i=1/L$$.
• $$w_\mathcal{R}=\sum_{i\in\mathcal{R}}w_i$$ is the sum of weights for subset $$\mathcal{R}$$.
• $$|\mathcal{R}|$$ gives the number of p-values in subset $$\mathcal{R}$$.
• $$\alpha_{|\mathcal{R}|}$$ and $$\alpha_{L}$$ are significance thresholds provided by the Landau distribution (Table 1).
In version 2.0 of the harmonicmeanp R package, the main function p.hmp is updated to take an additional argument, L, which sets the total number of p-values. If argument L is omitted, a warning is issued and L is assumed to equal the length of the first argument, p, preserving previous behaviour. Please update the R package.

An updated tutorial is available as a vignette in the R package and online here: http://www.danielwilson.me.uk/harmonicmeanp/hmpTutorial.html

### Why does this matter?

The family-wise error rate (FWER) controls the probability of falsely rejecting any null hypotheses, or groups of null hypotheses, when they are true. The strong-sense FWER maintains control even when some null hypotheses are false, thereby offering control across much broader and more relevant scenarios.

Using the more lenient threshold $$\alpha_{|\mathcal{R}|}$$ rather than the corrected threshold $$\alpha_L$$, both derived via Table 1 of the paper from the desired ssFWER $$\alpha$$, means the ssFWER is not controlled at the expected rate.

Tests with small numbers of p-values are far more likely to be affected in practice. In particular, individual p-values should be assessed against the threshold $$\alpha_{L}/L$$ when the HMP is used, not the more lenient $$\alpha_{1}/L$$ nor the still more lenient $$\alpha/L$$ (assuming equal weights). This shows that there is a cost to using the HMP compared to Bonferroni correction in the evaluation of individual p-values. For one billion tests $$\left(L=10^9\right)$$ and a desired ssFWER of $$\alpha=0.01$$, the fold difference in thresholds from Table 1 would be $$\alpha/\alpha_L=0.01/0.008=1.25$$.

However, it remains the case that HMP is much more powerful than Bonferroni for assessing the significance of groups of hypotheses. This is the motivation for using the HMP, and combined tests in general, because the power to find significant groups of hypotheses will be much higher than the power to detect significant individual hypotheses when the total number of tests (L) is large and the aim is to control the ssFWER.

### How does it affect the paper?

I have submitted a request to correct the paper to PNAS. It is up to the editors whether to agree to this request. A copy of the published paper, annotated with the requested corrections, is available here: http://www.danielwilson.me.uk/files/wilson_2019_annotated_corrections.pdf. Please use Adobe Reader to properly view the annotations and the embedded corrections to Figures 1 and 2.

### Where did the error come from?

Page 11 of the supplementary information gave a correct version of the full closed testing procedure that controls the ssFWER (Equation 37). However, it went on to erroneously claim that "one can apply weighted Bonferroni correction to make a simple adjustment to Equation 6 by substituting $$\alpha_{|\mathcal{R}|}$$ for $$\alpha$$." This reasoning would only be valid if the subsets of p-values to be combined were pre-selected and did not overlap. However, this would no longer constitute a flexible multilevel test in which every combination of p-values can be tested while controlling the ssFWER. The examples in Figures 1 and 2 pursued multilevel testing, in which the same p-values were assessed multiple times in subsets of different sizes, and in partially overlapping subsets of equal sizes. For the multilevel test, a formal shortcut to Equation 37, which makes it computationally practicable to control the ssFWER, is required. The simplest such shortcut procedure is the corrected test
$$\overset{\circ}{p}_\mathcal{R} \leq \alpha_{L}\,w_\mathcal{R}$$
One can show this is a valid multilevel test because if $$\overset{\circ}{p}_\mathcal{R}\leq\alpha_L\,w_\mathcal{R}$$ then $$\overset{\circ}{p}=\left(w_\mathcal{R}\,\overset{\circ}{p}^{-1}_\mathcal{R}+w_{\mathcal{R}^\prime}\,\overset{\circ}{p}^{-1}_{\mathcal{R}^\prime}\right)^{-1} \leq w^{-1}_\mathcal{R}\,\overset{\circ}{p}_\mathcal{R}\leq\alpha_L$$an argument that mirrors the logic of Equation 7 for direct interpretation of the HMP, which is not affected by this correction.