Document Detail

The novel "genomic pathway approach" to complex diseases: a reason for (over-)optimism?
MedLine Citation:
PMID:  19533849     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Examination of the genetic structure of complex diseases by a "genomic pathway approach"--which applies stepwise model selection to sets of more than 1000 polymorphisms in studies of several hundred subjects--has recently been proposed. Models constructed through extensive selection procedures may yield misleading test statistics and measures of predictive performance; we aimed to quantify the extent of such problems inherent to stepwise regression on the genomic pathway scale. METHODS: We performed permutation analyses and data-splitting approaches using one of the datasets examined in the paper that originally suggested this approach (n = 536; 1195 SNPs in 22 genes) (Lesnick et al. PLoS Genet. 2007;3:e98). RESULTS: The P values for the genetic effects produced by standard testing severely overestimated the significance, resulting in our example in a standard P value of 3.5 x 10(-69) and a permutation P of 0.003 (95% confidence interval = 0.001 to 0.009). Furthermore, the apparent validity as measured by the area under the receiver operating characteristic curve in 90% training datasets (0.935 [interquartile range = 0.918-0.951]) was extremely overoptimistic when compared with the validity estimated from the excluded 10% validation subsets (0.564 [0.518-0.614]). This validated area under the receiver operating characteristic curve was lower than for models predicting case/control status solely from age and sex while excluding any genetic effects (median difference = -0.040 [95% confidence interval = -0.049 to -0.031]). CONCLUSIONS: The application of stepwise model selection on the genomic pathway scale--at least in the simple form currently put forward--is prone to yield highly misleading results. We provide pointers to some promising alternatives.
Lutz P Breitling; Ewout W Steyerberg; Hermann Brenner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Epidemiology (Cambridge, Mass.)     Volume:  20     ISSN:  1531-5487     ISO Abbreviation:  Epidemiology     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-16     Completed Date:  2009-09-24     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9009644     Medline TA:  Epidemiology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  500-7     Citation Subset:  IM    
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Bergheimer St. 20, D-69115 Heidelberg, Germany.
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MeSH Terms
Genetic Predisposition to Disease*
Genetics, Medical
Odds Ratio
Polymorphism, Single Nucleotide*
Comment In:
Epidemiology. 2009 Jul;20(4):508-11   [PMID:  19525687 ]

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