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=== Summary of discussion from ESP rare variant working group ===
The rare variant working group within ESP has discussed the issue of
rare variant tests on several conference calls. The end result is
that we recommend selecting one test from each of these three
categories;
1. Aggregate tests (typically with 1% threshold, nonsynonymous SNPs
only, with meta-analysis across different ethnic groups)
2. Tests that allow for risk and/or protective variants (again,
probably 1% threshold, nonsynonymous SNPs only, with meta-analysis
across different ethnic groups)
3. Weighted tests that allow incorporation of more common variants
(possibly apply 5% threshold?, nonsynonymous only, etc.)
A brief summary of the RV discussion;
- Permutations (where we permute phenotype while maintaining ethnic
group) will likely be required to get empirical p-values. These RV
tests typically provide conservative p-values (deflated QQ plot), but
not always. Thus, a computationally intensive test will not be
practical for performing large numbers of permutations (at least
1000).
- Using too many tests will decrease the power overall because of
correction for family-wise error.
- Although we'd like to evaluate power and type I error rates of these
tests under a variety of genetic models, the reality is that we have
so few known positive examples it would be difficult to assess them
all in a fair way at this time. Instead, we expect to re-convene this
discussion group at a later date once some true positive associations
are identified.
- Shamil Sunyaev is performing a bake-off with some of these tests,
and we look forward to seeing his results in the future.
- PLINKSeq is on its way, but is likely a month away from release (end Feb 2011)
=== Summary of rare variant tests for sequence data ===
=== Summary of rare variant tests for sequence data ===
[http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq]
[http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq]
'''1) Aggregate tests using a cut off e.g. 1 % analyzing nonsynonymous variants to detect detrimental variants'''
'''1) Aggregate tests using a cut off e.g. 1 % analyzing nonsynonymous variants to detect detrimental variants'''
| RVE (rare variant exclusive) || Cohen & Hobb || || underpowered, [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq] |
| RVE (rare variant exclusive) || Cohen & Hobb || || underpowered, [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq] |
|}
|}
'''2) Aggregate tests for protective and detrimental variants (recommend 1% cutoff)'''
'''2) Aggregate tests for protective and detrimental variants (recommend 1% cutoff)'''
| EMMPAT* || [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978703/pdf/pgen.1001202.pdf King et al. 2010] || http://home.uchicago.edu/~crk8e/papersup.html || |
| EMMPAT* || [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978703/pdf/pgen.1001202.pdf King et al. 2010] || http://home.uchicago.edu/~crk8e/papersup.html || |
|}
|}
'''3) Analyzing common and rare variants together (could down-weight or threshold common variants)'''
'''3) Analyzing common and rare variants together (could down-weight or threshold common variants)'''
| MENDEL* || [http://www.ncbi.nlm.nih.gov/pubmed/21121038 Zhou et al. 2011] || http://www.genetics.ucla.edu/software/download?package=1 || |
| MENDEL* || [http://www.ncbi.nlm.nih.gov/pubmed/21121038 Zhou et al. 2011] || http://www.genetics.ucla.edu/software/download?package=1 || |
|}
|}
'''4.) Analyze higher frequency rare variants >1% individually'''
'''4.) Analyze higher frequency rare variants >1% individually'''
Use same regression frame work which has been used for common variants*
Use same regression frame work which has been used for common variants*
Use meta analysis to combine results from sequence data and imputed genotypes to increase power*
Use meta analysis to combine results from sequence data and imputed genotypes to increase power*
'''Additional tests'''
'''Additional tests'''
