umu.sePublications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
A fully adjusted two-stage procedure for rank-normalization in genetic association studies
Show others and affiliations
2019 (English)In: Genetic Epidemiology, ISSN 0741-0395, E-ISSN 1098-2272, Vol. 43, no 3, p. 263-275Article in journal (Refereed) Published
Abstract [en]

When testing genotype–phenotype associations using linear regression, departure of the trait distribution from normality can impact both Type I error rate control and statistical power, with worse consequences for rarer variants. Because genotypes are expected to have small effects (if any) investigators now routinely use a two‐stage method, in which they first regress the trait on covariates, obtain residuals, rank‐normalize them, and then use the rank‐normalized residuals in association analysis with the genotypes. Potential confounding signals are assumed to be removed at the first stage, so in practice, no further adjustment is done in the second stage. Here, we show that this widely used approach can lead to tests with undesirable statistical properties, due to both combination of a mis‐specified mean–variance relationship and remaining covariate associations between the rank‐normalized residuals and genotypes. We demonstrate these properties theoretically, and also in applications to genome‐wide and whole‐genome sequencing association studies. We further propose and evaluate an alternative fully adjusted two‐stage approach that adjusts for covariates both when residuals are obtained and in the subsequent association test. This method can reduce excess Type I errors and improve statistical power.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019. Vol. 43, no 3, p. 263-275
Keywords [en]
rank-normalization, rare variants, whole-genome sequencing
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:umu:diva-157743DOI: 10.1002/gepi.22188ISI: 000461058300003PubMedID: 30653739Scopus ID: 2-s2.0-85060217416OAI: oai:DiVA.org:umu-157743DiVA, id: diva2:1303439
Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-04-09Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMedScopus

Authority records BETA

Shungin, Dmitry

Search in DiVA

By author/editor
Shungin, Dmitry
By organisation
Department of Odontology
In the same journal
Genetic Epidemiology
Medical Genetics

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 164 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf