Predicting genetic predisposition in humans: the promise of whole-genome markers

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Abstract

Although genome-wide association studies have identified markers that are associated with various human traits and diseases, our ability to predict such phenotypes remains limited. A perhaps overlooked explanation lies in the limitations of the genetic models and statistical techniques commonly used in association studies. We propose that alternative approaches, which are largely borrowed from animal breeding, provide potential for advances. We review selected methods and discuss the challenges and opportunities ahead.

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Acknowledgements

We are grateful to K. Grimes, A. Vazquez, Y. Klimentidis and S. Cofield for their helpful comments on this paper.

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Competing interests

Gustavode los Campos has served as a consultant to CIMMYT and Aviagen; both organizations work with genomic-enabled prediction of genetic values for plant and poultry breeding, respectively. Daniel Gianola serves on the International Scientific Advisory Board of Aviagen. David Allison has received numerous grants, consulting fees and donations from non-profit and for profit entities, some of which may have interests in the genomic prediction of phenotypes.

Supplementary information

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Online Box: Probit Model (PDF 99 kb)

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FURTHER INFORMATION

Gustav de los Campo's homepage

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Nature Reviews Genetics series on study designs

Nature Reviews Genetics series on Modelling

Nature Reviews Genetics series on Genome-wide association studies

Glossary

Bayesian estimation

Bayesian inferences are based on the posterior distribution of the unknowns given the data. Following Bayes' rule, this distribution is proportional to the product of the distribution of the data given the unknowns times the prior distribution of the unknowns.

Basis function

In regression analysis, basis functions are functions of predictors used to construct the regression. Polynomials, exponential and logarithm are examples of basis functions commonly used for parametric regressions.

Censored phenotype

Censoring occurs when, for some individuals, the phenotypic information consists of bounds but the actual phenotypic value is unknown. This is commonly observed in longevity studies when, at the time of analysis, some patients may still be alive.

Genomic medicine

The use of genome information in the prevention, diagnosis and treatment of disorders.

Goodness of fit

A measure of how well a model fits the data in a training sample. The log likelihood and R-squared statistic are commonly used measures of goodness of fit. The residual sum of squares is a commonly used measure of lack of fit.

LASSO

The Least Absolute Shrinkage and Selection Operator23 is a penalized estimation method commonly used in regression. The penalty function in LASSO is the sum of the absolute value of the regression coefficients. LASSO performs variable selection and shrinkage simultaneously.

Objective function

The function whose value is minimized or maximized in an optimization problem.

Ordinary least squares

The ordinary least squares estimates of parameters in a regression model are obtained by minimizing the residual sum of squares of the regression.

Over-fitting

A term used to describe the situation in which a model fits the training data well but fails to perform well when used to predict outcomes of a collection of subjects (testing data) that was not used to fit the model.

Parametric regression model

A regression model in which the regression function is set to have a known functional form (for example, a polynomial).

Penalized estimation

Penalized estimates are commonly used in situations in which the number of unknowns is large with respect to the number of records. Penalized estimates are obtained by solving an optimization problem whose objective function embeds a compromise between a goodness-of-fit measure and a measure of model complexity or penalty function.

Quantitative genetic theory

Genetic, mathematical and statistical models used to study traits that are affected by a large number of genes.

Regression model

A statistical model used to describe relationships (for example, a conditional mean) between a response variable and a set of predictors through a regression function involving some parameter(s) to be estimated from data.

Semi-parametric regression model

A regression model in which the regression function is not assumed to be a member of a parametric family.

Shrinkage

In standard estimation methods (for example, maximum likelihood or OLS) estimates are obtained by optimizing with respect to a goodness-of-it or lack-of-fit measure. Relative to these estimates, Bayesian and penalized estimates are shrunk towards some values (typically zero). This prevents over-fitting and, under certain conditions, may reduce mean-squared error of estimates and predictions.

Training data

The data set used to fit a model.

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