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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 === |
| | | |
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| | | |
| * indicates applicability to quantitative data | | * indicates applicability to quantitative data |
− | ? indicates possible applicability to quantitative data with adaptation
| + | |
− | Blue font indicates implementation in upcoming PLINKSeq release (http://atgu.mgh.harvard.edu/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''' |
| + | |
| + | {| width="75%" cellspacing="0" cellpadding="5" border="1" |
| + | |- |
| + | ! scope="col" align="left" | Test Name |
| + | ! scope="col" align="left" | Reference |
| + | ! scope="col" align="left" | Software |
| + | ! scope="col" align="left" | Notes |
| + | |- |
| + | | CMC/T1 test* || [http://www.ncbi.nlm.nih.gov/pubmed/18691683 Li & Leal, 2008] |
| + | | |
| + | | [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq] |
| + | |- |
| + | | KBAC || [http://www.ncbi.nlm.nih.gov/pubmed/20976247 Liu & Leal, 2010] || |
| + | | [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq] |
| + | |- |
| + | | 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, [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq] | |
| + | |- |
| + | | WSS || [http://www.ncbi.nlm.nih.gov/pubmed/19214210 Madsen & Browning, 2009] || |
| + | | with 1% cutoff, [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq] |
| + | |- |
| + | | CMAT || [http://www.ncbi.nlm.nih.gov/pubmed/21070896 Zawistowski et al. 2010] || || |
| + | |- |
| + | | ANRV/GRANVIL* || [http://www.ncbi.nlm.nih.gov/pubmed/19810025 Morris & Zeggini] || || |
| + | |- |
| + | | RARECOVER || [http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000954 Bhati et al. 2010] || || |
| + | |- |
| + | | CCRaVAT and QuTie* || [http://www.ncbi.nlm.nih.gov/pubmed/20964851 Lawrence et al. 2010] |
| + | | http://www.sanger.ac.uk/resources/software/rarevariant/ || |
| + | |- |
| + | | RVE (rare variant exclusive) || Cohen & Hobbs || |
| + | | underpowered, [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq] |
| + | |} |
| + | |
| + | |
| + | |
| + | '''2) Aggregate tests for protective and detrimental variants (recommend 1% cutoff)''' |
| + | |
| + | {| width="75%" cellspacing="0" cellpadding="5" border="1" |
| + | |- |
| + | ! scope="col" align="left" | Test Name |
| + | ! scope="col" align="left" | Reference |
| + | ! scope="col" align="left" | Software |
| + | ! scope="col" align="left" | Notes |
| + | |- |
| + | | C-alpha || [Neale et al., submitted] || |
| + | | [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq] |
| + | |- |
| + | | Ionita-Laza & Lange |
| + | | [http://www.plosgenetics.org/article/info%3Adoi%2F10.1371%2Fjournal.pgen.1001289 Ionita-Laza & Lange, 2011] || || | |
| + | |- |
| + | | DASH* || [http://www.ncbi.nlm.nih.gov/pubmed/20413981 Han & Pan] || || Computational burden |
| + | |- |
| + | | 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 |
| + | |- |
| + | | WHaIT || [http://www.ncbi.nlm.nih.gov/pubmed/21055717 Li et al. 2010] |
| + | | http://csg.sph.umich.edu//yli/whait/ || |
| + | |- |
| + | | 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)''' |
| | | |
| {| width="75%" cellspacing="0" cellpadding="5" border="1" | | {| width="75%" cellspacing="0" cellpadding="5" border="1" |
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| ! scope="col" align="left" | Notes | | ! scope="col" align="left" | Notes |
| |- | | |- |
− | | CMC/T1 test* || Li & Leal, 2008 || || || | + | | WSS || [http://www.ncbi.nlm.nih.gov/pubmed/19214210 Madsen & Browning, 2009] || |
| + | | with 1% or 5% cutoff, [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq] |
| + | |- |
| + | | RARECOVER |
| + | | [http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000954 Bhati et al. 2010] || || |
| + | |- |
| + | | Step-Up Collapsing* |
| + | | [http://www.plosone.org/article/info:doi/10.1371/journal.pone.0013584 Hoffman et al. 2010] || |
| + | | [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq] |
| + | |- |
| + | | CMC/T5 test* || [http://www.ncbi.nlm.nih.gov/pubmed/18691683 Li & Leal, 2008] || |
| + | | [http://atgu.mgh.harvard.edu/plinkseq/ Will be implemented in PlinkSeq] |
| |- | | |- |
− | | KBAC || Liu & Leal, 2010 || || || | + | | 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''' |
| + | 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* |
| + | |
| + | '''Additional tests''' |
| + | |
| + | {| width="75%" cellspacing="0" cellpadding="5" border="1" |
| + | |- |
| + | ! scope="col" align="left" | Test Name |
| + | ! scope="col" align="left" | Reference |
| + | ! scope="col" align="left" | Software |
| + | ! scope="col" align="left" | Notes |
| |- | | |- |
− | | VT* || Price et al., 2010 || http://genetics.bwh.harvard.edu/rare_variants/ || Incorporating functional weights but not VT | + | | Logic regression* || [http://kooperberg.fhcrc.org/papers/2001gaw.pdf Kooperberg et al. 2001] || || |
| |- | | |- |
− | | WSS || Madsen & Browning, 2009 || || with 1% cutoff | + | | Sequence diversity || Anderson et al. 2006 || || |
| |- | | |- |
− | | CMAT || Zawistowski et al. 2010 || | + | | Sequence dissimilarity* || Schork et al. 2008, Wessel et al. 2006 || || |
| |- | | |- |
| + | | Ridge regression * || [http://www.cell.com/AJHG/abstract/S0002-9297(08)00091-8 Malo et al. 2008] || || |
| |} | | |} |