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Rare variant tests (view source)

Revision as of 11:35, 2 February 2017

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→‎Summary of rare variant tests for sequence data
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=== Summary of discussion from ESP rare variant working group ===
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The rare variant working group within ESP has discussed the issue of
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rare variant tests on several conference calls.  The end result is
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that we recommend selecting one test from each of these three
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categories;
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1. Aggregate tests (typically with 1% threshold, nonsynonymous SNPs
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only, with meta-analysis across different ethnic groups)
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2. Tests that allow for risk and/or protective variants (again,
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probably 1% threshold, nonsynonymous SNPs only, with meta-analysis
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across different ethnic groups)
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3. Weighted tests that allow incorporation of more common variants
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(possibly apply 5% threshold?, nonsynonymous only, etc.)
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A brief summary of the RV discussion;
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- Permutations (where we permute phenotype while maintaining ethnic
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group) will likely be required to get empirical p-values.  These RV
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tests typically provide conservative p-values (deflated QQ plot), but
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not always.  Thus, a computationally intensive test will not be
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practical for performing large numbers of permutations (at least
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1000).
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- Using too many tests will decrease the power overall because of
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correction for family-wise error.
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- Although we'd like to evaluate power and type I error rates of these
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tests under a variety of genetic models, the reality is that we have
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so few known positive examples it would be difficult to assess them
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all in a fair way at this time.  Instead, we expect to re-convene this
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discussion group at a later date once some true positive associations
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are identified.
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- Shamil Sunyaev is performing a bake-off with some of these tests,
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and we look forward to seeing his results in the future.
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- PLINKSeq is on its way, but is likely a month away from release (end Feb 2011)
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=== Summary of rare variant tests for sequence data  ===
 
=== Summary of rare variant tests for sequence data  ===
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  * indicates applicability to quantitative data
 
  * indicates applicability to quantitative data
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? indicates possible applicability to quantitative data with adaptation
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Blue font indicates implementation in upcoming PLINKSeq release (http://atgu.mgh.harvard.edu/plinkseq/)
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! scope="col" align="left" | Reference
 
! scope="col" align="left" | Reference
 
! scope="col" align="left" | Software
 
! scope="col" align="left" | Software
−
! scope="col" align="left" | Notes |
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! scope="col" align="left" | Notes  
 
|-
 
|-
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| CMC/T1 test* || [http://www.ncbi.nlm.nih.gov/pubmed/18691683 Li & Leal, 2008] || || |
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| CMC/T1 test* || [http://www.ncbi.nlm.nih.gov/pubmed/18691683 Li & Leal, 2008]  
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|
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| [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq]
 
|-
 
|-
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| KBAC || [http://www.ncbi.nlm.nih.gov/pubmed/20976247 Liu & Leal, 2010] || || |
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| KBAC || [http://www.ncbi.nlm.nih.gov/pubmed/20976247 Liu & Leal, 2010] ||  
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| [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq]
 
|-
 
|-
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| VT* || [http://www.ncbi.nlm.nih.gov/pubmed/20471002 Price et al., 2010] || http://genetics.bwh.harvard.edu/rare_variants/ || Incorporating functional weights but not VT |
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| VT* || [http://www.ncbi.nlm.nih.gov/pubmed/20471002 Price et al., 2010]  
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| http://genetics.bwh.harvard.edu/rare_variants/  
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| Incorporating functional weights but not VT, [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq] |
 
|-
 
|-
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| WSS || [http://www.ncbi.nlm.nih.gov/pubmed/19214210 Madsen & Browning, 2009] || || with 1% cutoff |
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| WSS || [http://www.ncbi.nlm.nih.gov/pubmed/19214210 Madsen & Browning, 2009] ||  
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| with 1% cutoff, [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq]
 
|-
 
|-
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| CMAT || [http://www.ncbi.nlm.nih.gov/pubmed/21070896 Zawistowski et al. 2010] || || |
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| CMAT || [http://www.ncbi.nlm.nih.gov/pubmed/21070896 Zawistowski et al. 2010] || ||  
 
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|-
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| ANRV/GRANVIL* || [http://www.ncbi.nlm.nih.gov/pubmed/19810025 Morris & Zeggini] || || |
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| ANRV/GRANVIL* || [http://www.ncbi.nlm.nih.gov/pubmed/19810025 Morris & Zeggini] || ||  
 
|-
 
|-
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| RARECOVER || [http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000954 Bhati et al. 2010] || || |
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| RARECOVER || [http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000954 Bhati et al. 2010] || ||  
 
|-
 
|-
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| CCRaVAT and QuTie* || [http://www.ncbi.nlm.nih.gov/pubmed/20964851 Lawrence et al. 2010] || http://www.sanger.ac.uk/resources/software/rarevariant/ || |
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| CCRaVAT and QuTie* || [http://www.ncbi.nlm.nih.gov/pubmed/20964851 Lawrence et al. 2010]  
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| http://www.sanger.ac.uk/resources/software/rarevariant/ ||  
 
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|-
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| RVE (rare variant exclusive) || Cohen & Hobb || || underpowered |
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| RVE (rare variant exclusive) || Cohen & Hobbs ||  
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| underpowered, [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq]
 
|}
 
|}
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'''2)  Aggregate tests for protective and detrimental variants (recommend 1% cutoff)'''
 
'''2)  Aggregate tests for protective and detrimental variants (recommend 1% cutoff)'''
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! scope="col" align="left" | Reference
 
! scope="col" align="left" | Reference
 
! scope="col" align="left" | Software
 
! scope="col" align="left" | Software
−
! scope="col" align="left" | Notes |
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! scope="col" align="left" | Notes  
 
|-
 
|-
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| C-alpha || [Neale et al., submitted] ||  || |
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| C-alpha || [Neale et al., submitted] ||   
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| [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq]
 
|-
 
|-
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| Ionita-Laza & Lange || [http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1001289 Ionita-Laza & Lange, 2011] || || |
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| Ionita-Laza & Lange  
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| [http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1001289 Ionita-Laza & Lange, 2011] || || |
 
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|-
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| DASH* || [http://www.ncbi.nlm.nih.gov/pubmed/20413981 Han & Pan] || || Computational burden |
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| DASH* || [http://www.ncbi.nlm.nih.gov/pubmed/20413981 Han & Pan] || || Computational burden  
 
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|-
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| SKAT* || [http://www.ncbi.nlm.nih.gov/pubmed/20560208 Wu et al., 2010] || http://www.hsph.harvard.edu/~xlin/software.html || For some kernel choices, need to code 0=major homozygote, 1=het, 2-minor homozygote |
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| SKAT* || [http://www.ncbi.nlm.nih.gov/pubmed/20560208 Wu et al., 2010]  
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| http://www.hsph.harvard.edu/~xlin/software.html  
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| For some kernel choices, need to code 0=major homozygote, 1=het, 2-minor homozygote  
 
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|-
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| WHaIT || [http://www.ncbi.nlm.nih.gov/pubmed/21055717 Li et al. 2010] || http://www.sph.umich.edu/csg/yli/whait/ || |
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| WHaIT || [http://www.ncbi.nlm.nih.gov/pubmed/21055717 Li et al. 2010]  
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| http://csg.sph.umich.edu//yli/whait/ ||  
 
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|-
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| 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 || |
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| EMMPAT*  
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| [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978703/pdf/pgen.1001202.pdf King et al. 2010]  
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| http://home.uchicago.edu/~crk8e/papersup.html ||  
 
|}
 
|}
   −
'''Analyzing common and rare variants together (could down-weight or threshold common variants)'''
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'''3) Analyzing common and rare variants together (could down-weight or threshold common variants)'''
    
{| width="75%" cellspacing="0" cellpadding="5" border="1"
 
{| width="75%" cellspacing="0" cellpadding="5" border="1"
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! scope="col" align="left" | Reference
 
! scope="col" align="left" | Reference
 
! scope="col" align="left" | Software
 
! scope="col" align="left" | Software
−
! scope="col" align="left" | Notes |
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! scope="col" align="left" | Notes
 
|-
 
|-
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| WSS || [http://www.ncbi.nlm.nih.gov/pubmed/19214210 Madsen & Browning, 2009] || || with 1% or 5% cutoff |
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| WSS || [http://www.ncbi.nlm.nih.gov/pubmed/19214210 Madsen & Browning, 2009] ||  
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| with 1% or 5% cutoff, [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq]
 
|-
 
|-
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| RARECOVER || [http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000954 Bhati et al. 2010] || || |
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| RARECOVER  
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| [http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000954 Bhati et al. 2010] || ||  
 
|-
 
|-
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| Step-Up Collapsing* || [http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013584
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| Step-Up Collapsing*  
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| [http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013584 Hoffman et al. 2010] ||
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| [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq]
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|-
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| CMC/T5 test* || [http://www.ncbi.nlm.nih.gov/pubmed/18691683 Li & Leal, 2008] || 
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| [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq]
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|-
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| MENDEL* || [http://www.ncbi.nlm.nih.gov/pubmed/21121038 Zhou et al. 2011]
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| http://www.genetics.ucla.edu/software/download?package=1 ||
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|}
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'''4.) Analyze higher frequency rare variants >1% individually'''
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                  Use same regression frame work which has been used for common variants*
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                  Use meta analysis to combine results from sequence data and imputed genotypes to increase power*
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'''Additional tests'''
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{| width="75%" cellspacing="0" cellpadding="5" border="1"
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|-
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! scope="col" align="left" | Test Name
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! scope="col" align="left" | Reference
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! scope="col" align="left" | Software
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! scope="col" align="left" | Notes
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|-
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| Logic regression* || [http://kooperberg.fhcrc.org/papers/2001gaw.pdf Kooperberg et al. 2001] ||  ||
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|-
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| Sequence diversity || Anderson et al. 2006 || ||
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|-
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| Sequence dissimilarity* || Schork et al. 2008, Wessel et al. 2006 || ||
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|-
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| Ridge regression * || [http://www.cell.com/AJHG/abstract/S0002-9297(08)00091-8 Malo et al. 2008] || ||
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|}
Ppwhite
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