Evidence map›Paper›PMID 12587097›Full record

ArticleAmerican journal of human genetics2003

Undetected genotyping errors cause apparent overtransmission of common alleles in the transmission/disequilibrium test.

Adele A Mitchell, David J Cutler, Aravinda Chakravarti

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in American journal of human genetics, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 72 papers, 15 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
72citing papers in PubMed, 15 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

72 citing papers in PubMed, 15 syntheses or guidelines pooled it.

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  3. Comprehensive assessment of the association between DNA repair gene XRCC3 Thr241Met polymorphism and leukemia risk.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2014
    Pooled it
  4. DNA repair gene XRCC3 polymorphisms and bladder cancer risk: a meta-analysis.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2014
    Pooled it
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  6. Current evidence on the relationship between SNP309 polymorphism in the MDM2 gene and colorectal cancer risk.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2013
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  11. TP53 Arg72Pro polymorphism and endometrial cancer risk: a meta-analysis.Medical oncology (Northwood, London, England) · 2011
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12 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

3 authors.

Adele A MitchellMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD 21287, USA.
David J Cutler
Aravinda Chakravarti

Funding

Predoctoral Training Program in Human GeneticsT32GM007814 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 1985 to 2021
$10.6M
GENETIC EPIDEMIOLOGY OF HYPERTENSION--GENOMIC CORESU10HL054466 · NHLBI · CASE WESTERN RESERVE UNIVERSITY · PI CHAKRAVARTI, ARAVINDA · 1995 to 1999
–
NHLBI NIH HHS 5U10HL54466-08NHLBI NIH HHS U10 HL054466NIGMS NIH HHS 5T32GM07814NIGMS NIH HHS T32 GM007814
6 · The paper itself

Abstract

The transmission/disequilibrium test (TDT), a family-based test of linkage and association, is a popular and intuitive statistical test for studies of complex inheritance, as it is nonparametric and robust to population stratification. We carried out a literature search and located 79 significant TDT-derived associations between a microsatellite marker allele and a disease. Among these, there were 31 (39%) in which the most common allele was found to exhibit distorted transmission to affected offspring, implying that the allele may be associated with either susceptibility to or protection from a disease. In 27 of these 31 studies (87%), the most common allele appeared to be overtransmitted to affected offspring (a risk factor), and, in the remaining 4 studies, the most common allele appeared to be undertransmitted (a protective factor). In a second literature search, we identified 92 case-control studies in which a microsatellite marker allele was found to have significantly different frequencies in case and control groups. Of these, there were 37 instances (40%) in which the most common allele was involved. In 12 of these 37 studies (32%), the most common allele was enriched in cases relative to controls (a risk factor), and, in the remaining 25 studies, the most common allele was enriched in controls (a protective factor). Thus, the most common allele appears to be a risk factor when identified through the TDT, and it appears to be protective when identified through case-control analysis. To understand this phenomenon, we incorporated an error model into the calculation of the TDT statistic. We show that undetected genotyping error can cause apparent transmission distortion at markers with alleles of unequal frequency. We demonstrate that this distortion is in the direction of overtransmission for common alleles. Therefore, we conclude that undetected genotyping errors may be contributing to an inflated false-positive rate among reported TDT-derived associations and that genotyping fidelity must be increased.

Indexed as

GenotypeLinkage DisequilibriumMutationAllelesGenetic VariationHumansModels, GeneticModels, StatisticalReproducibility of Results

Identifiers

PMID12587097
PMCPMC1180236

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.