#pvalue

What is the p-Value in statistics? The p-value is one of the most important quantities in statistics for interpreting hypothesis tests. source

p value is probability that coefficient of variable is equal 0.

the higher probability (p-value), the higher chance that coefficient is equal 0 and hence the variable is not important.

Yesterday, I had the pleasure of reading an interesting GWAS of Lewy body dementia (LBD) published in Nature Genetics. LBD shares pathological and clinical features with Alzheimer’s disease (AD) and Parkinson’s dementia (PD). So, I was curious to know how the GWAS results of LBD compare to that of AD and PD. As expected, the APOE locus towered over all other loci.  The effect size of the APOE locus was OR-2.46. This is much smaller than the APOE’s effect size for AD. For e.g. this study reports OR-4.6 for AD in heterozygous APOE-e4 carriers and OR-25.4 in homozygous APOE-e4 carriers. So, although APO-E locus seems to account for the largest number of LBD cases (smallest P value and common allele frequency) in this study, its penetrance is markedly lower compared to AD.  

Whenever I read a GWAS, the first thing I look for is which locus has the largest effect size. This cannot be identified using a Manhattan plot, as P values do not reflect the effect sizes. The summary statistics table in the paper showed that a chromosome 1 locus had the largest effect size. At this locus, the index variant is a missense variant in gene GBA, which codes for a lysosomal enzyme glucocerebrosidase. (This is a known locus. A high penetrance of up to ~33% was reported for GBA mutations in LBD in Ashkenazi Jews.) Despite having the largest effect size, this locus was not the one with the smallest P value. Because, this variant is relatively rare and so its P value was not as smaller as APOE’s. This is something that I often emphasise in twitter. A highly penetrant rare variant can have less significant P value than a moderately penetrant common variant. This doesn’t mean that the rare variant is less important than the common variant. It’s in fact the opposite. Variants with larger effect sizes point us to the core disease pathways. In the current study, for e.g., the GBA locus points us straight to the core pathology of LBD: lysosomal dysfunction.

Another perfect example for the effect size vs P value debate is the ACAN locus identified in the 2010 GWAS of height published by the GIANT consortium. I’ve written a twitter thread on this. This locus had the largest effect size, but did not tower tall enough to grab the authors’ attention (a word search for “ACAN” will reveal zero results in this paper’s main text.) The authors wouldn’t had any idea, I believe, that 10 years later, two independent research teams (this and this) will show that the ACAN locus’s large effect association was driven by a variable number tandem repeat (VNTR) within ACAN. The effect size of this VNTR is astonishingly large, in fact, one of the largest ever reported for height. Also, the gene ACAN codes for a cartilage protein thereby falling in the core biological pathway of height. Fascinating, isn’t it ?

BASP journal banning p-value

David Trafimow and Michael Marks,  Editorial, Basic and Applied Social Psychology 37:1–2, 2015

http://www.medicine.mcgill.ca/epidemiology/Joseph/courses/EPIB-621/BASP2015.pdf

See Nassim Taleb:

https://www.youtube.com/watch?v=D6CxfBMUf1o

https://www.youtube.com/watch?v=8qrfSh07rT0

https://arxiv.org/pdf/1603.07532.pdf