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A cautionary note on using secondary phenotypes in neuroimaging genetic studies.

ABSTRACT: Almost all genome-wide association studies (GWASs), including Alzheimer's Disease Neuroimaging Initiative (ADNI), are based on the case-control study design, implying that the resulting case-control data are likely a biased, not random, sample of the target population. Although association analysis of the disease (e.g. Alzheimer's disease in the ADNI) can be conducted using a standard logistic regression by ignoring the biased case-control sampling, a standard linear regression analysis on a secondary phenotype (e.g. any neuroimaging phenotype in the ADNI) may in general lead to biased inference, including biased parameter estimates, inflated Type I errors and reduced power for association testing. Despite of this well known result in genetic epidemiology, to our surprise, all the published studies on secondary phenotypes with the ADNI data have ignored this potential problem. Here we aim to answer whether such a standard analysis of a secondary phenotype is valid or problematic with the ADNI data. Through both real data analyses and simulation studies, we found that, strikingly, such an analysis was generally valid (with only small biases or slightly inflated Type I errors) for the ADNI data, though cautions must be taken when analyzing other data. We also illustrate applications and possible problems of two methods specifically developed for valid analysis of secondary phenotypes.

SUBMITTER: Kim J

PROVIDER: S-EPMC4604049 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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A cautionary note on using secondary phenotypes in neuroimaging genetic studies.

Kim Junghi J Pan Wei W

NeuroImage 20150726

Almost all genome-wide association studies (GWASs), including Alzheimer's Disease Neuroimaging Initiative (ADNI), are based on the case-control study design, implying that the resulting case-control data are likely a biased, not random, sample of the target population. Although association analysis of the disease (e.g. Alzheimer's disease in the ADNI) can be conducted using a standard logistic regression by ignoring the biased case-control sampling, a standard linear regression analysis on a sec ...[more]

PMID: 26220747

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Project description:BACKGROUND:Plasmodium vivax is the most widespread of the human malaria parasites in terms of geography, and is thought to present unique challenges to local efforts aimed at control and elimination. Parasite molecular markers can provide much needed data on P. vivax populations, but few such markers have been critically evaluated. One marker that has seen extensive use is the gene encoding merozoite surface protein 3-alpha (MSP-3?), a blood-stage antigen known to be highly variable among P. vivax isolates. Here, a sample of complete msp-3? gene sequences is analysed in order to assess its utility as a molecular marker for epidemiologic investigations. METHODS:Amplification, cloning and sequencing of additional P. vivax isolates from different geographic locations, including a set of Venezuelan field isolates (n?=?10), yielded a sample of 48 complete msp-3? coding sequences. Characterization of standard population genetic measures of diversity, phylogenetic analysis, and tests for recombination were performed. This allowed comparisons to patterns inferred from the in silico simulation of a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) protocol used widely. RESULTS:The larger sample of MSP-3? diversity revealed incongruence between the observed levels of nucleotide polymorphism, which were high in all populations, and the pattern of PCR-RFLP haplotype diversity. Indeed, PCR-RFLP haplotypes were not informative of a population's genetic diversity and identical haplotypes could be produced from analogous bands in the commonly used protocol. Evidence of frequent and variable insertion-deletion mutations and recurrent recombination between MSP-3? haplotypes complicated the inference of genetic diversity patterns and reduced the phylogenetic signal. CONCLUSIONS:The genetic diversity of P. vivax msp-3? involves intragenic recombination events. Whereas the high genetic diversity of msp-3? makes it a promising marker for some epidemiological applications, the ability of msp-3? PCR-RFLP analysis to accurately track parasites is limited. Local studies of the circulating alleles are needed before implementing PCR-RFLP approaches. Furthermore, evidence from the global sample analysed here suggests such msp-3? PCR-RFLP methods are not suitable for broad geographic studies or tracking parasite populations for an extended period of time.

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A cautionary note on using secondary phenotypes in neuroimaging genetic studies.

Publications

A cautionary note on using secondary phenotypes in neuroimaging genetic studies.

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