Evaluation of approaches for estimating the accuracy of genomic prediction in plant breeding
 Sidi Boubacar Ould Estaghvirou^{1},
 Joseph O Ogutu^{1}Email author,
 Torben SchulzStreeck^{1, 2},
 Carsten Knaak^{2},
 Milena Ouzunova^{2},
 Andres Gordillo^{3} and
 HansPeter Piepho^{1}
DOI: 10.1186/1471216414860
© Ould Estaghvirou et al.; licensee BioMed Central Ltd. 2013
Received: 10 June 2013
Accepted: 22 November 2013
Published: 6 December 2013
Abstract
Background
In genomic prediction, an important measure of accuracy is the correlation between the predicted and the true breeding values. Direct computation of this quantity for real datasets is not possible, because the true breeding value is unknown. Instead, the correlation between the predicted breeding values and the observed phenotypic values, called predictive ability, is often computed. In order to indirectly estimate predictive accuracy, this latter correlation is usually divided by an estimate of the square root of heritability. In this study we use simulation to evaluate estimates of predictive accuracy for seven methods, four (1 to 4) of which use an estimate of heritability to divide predictive ability computed by crossvalidation. Between them the seven methods cover balanced and unbalanced datasets as well as correlated and uncorrelated genotypes. We propose one new indirect method (4) and two direct methods (5 and 6) for estimating predictive accuracy and compare their performances and those of four other existing approaches (three indirect (1 to 3) and one direct (7)) with simulated true predictive accuracy as the benchmark and with each other.
Results
The size of the estimated genetic variance and hence heritability exerted the strongest influence on the variation in the estimated predictive accuracy. Increasing the number of genotypes considerably increases the time required to compute predictive accuracy by all the seven methods, most notably for the five methods that require crossvalidation (Methods 1, 2, 3, 4 and 6). A new method that we propose (Method 5) and an existing method (Method 7) used in animal breeding programs were the fastest and gave the least biased, most precise and stable estimates of predictive accuracy. Of the methods that use crossvalidation Methods 4 and 6 were often the best.
Conclusions
The estimated genetic variance and the number of genotypes had the greatest influence on predictive accuracy. Methods 5 and 7 were the fastest and produced the least biased, the most precise, robust and stable estimates of predictive accuracy. These properties argue for routinely using Methods 5 and 7 to assess predictive accuracy in genomic selection studies.
Keywords
Genomic selection Ridgeregression BLUP Predictive accuracy Predictive ability Heritability SNP markers Zea mays Crossvalidation Plant breedingBackground
Genomic selection (GS) is a method for predicting genomic breeding values using molecular markers covering the whole genome [1–3]. GS is fast becoming popular in plant and animal breeding [1, 4, 5], because of recent advances in highthroughput marker technologies and accompanying reduction in the costs of genotyping.
The performance of genomic selection (GS) procedures is often assessed by kfold crossvalidation (CV) [6]. Accurate evaluation of the performance of genomic selection is difficult in practice because true breeding values are typically unknown. As result, simulation modeling is often used to generate breeding values as a basis for assessing the accuracy of genomic prediction [1]. Once the true breeding values are available, the accuracy of genomic prediction can be expressed as the correlation between the true and the predicted breeding values. In this paper, we use simulated true breeding values to directly compute the true correlation (accuracy) between the true and the predicted breeding values $\left({r}_{g,\widehat{g}}\right)$ as a benchmark for evaluating the performance of seven contending methods. Four of the seven methods (Methods 1 to 4) first estimate heritability H^{2}[7] and then divide the crossvalidation sample correlation between the predicted breeding values ($\widehat{g}$) and the observed phenotypic values (p), predictive ability, by the square root of heritability H^{2}[8, 9] to obtain an estimate of predictive accuracy ${r}_{\widehat{g},p}/H$. The remaining three methods (Methods 5 to 7) estimate the predictive accuracy directly without having to first estimate heritability, even though Method 5 also estimates heritability. Here, we investigate the relative merits of the seven methods for estimating predictive accuracy using simulated breeding values. For five of the seven methods for estimating predictive accuracy (Methods 1, 2, 3, 4 and 6), we comparatively evaluate their predictive accuracies using threefold crossvalidation. Of the seven methods, two direct methods (Methods 5 and 6) and one indirect method (Method 4) for estimating predictive accuracy are proposed and described here for the first time whereas the remaining four methods were obtained from the literature. Methods 1 to 3 assume uncorrelated genotypes in the model for estimating heritability but assume correlated genotypes in the model for estimating predictive ability.
Methods
We denote the standard deviation of a sample with s and that of a population with σ and the sample and population variance of the true genetic breeding values g with ${s}_{g}^{2}$ and ${\sigma}_{g}^{2}$, respectively. Further, we denote with r, ${r}_{\widehat{g},p}$, ρ and ρ_{g,p} the sample correlation, the sample correlation between the BLUP of g and the observed “phenotypes” p, the population correlation and the population correlation between the true genetic breeding values g and the observed “phenotypes” p, respectively. Also, we use ${r}_{g,\widehat{g}}$, ${s}_{g,\widehat{g}}$, ${s}_{\widehat{g}}^{2}$ and ${s}_{p}^{2}$ to denote the sample correlation between the true and the predicted genetic breeding values, the sample covariance between the true and the predicted breeding values, and the sample variance of the predicted breeding value and the phenotypic sample variance, respectively. In this paper, the sample will generally refer to a trial with n genotypes, real or simulated, assumed to have been obtained from an infinite population of genotypes.
True correlation
where $\overline{\widehat{g}}$ denotes the estimated mean of ${\widehat{g}}_{i}\left(i=1,\dots ,n\right)$, are sample variances of the true and the predicted breeding values, respectively. We take the unobservable correlation ${r}_{g,\widehat{g}}$ to be the main quantity of interest to the breeder or geneticist. Seven alternative procedures are evaluated, by simulation, regarding the accuracy and precision with which they are able to estimate ${r}_{g,\widehat{g}}.$
Twostage approaches
where y is the vector of the observed phenotypic values, μ is a vector containing the adjusted genotype means to be estimated from a model in which genotype enters as a fixed effect and X_{1} is an associated design matrix and f combines all the fixed, random design and error effects (replicates, blocks, etc.).
The first stage of the twostage approaches
At the first stage, means (μ) for the testcross genotypes are estimated using model (5) and submitted to the second stage. The adjusted means of the standard varieties are excluded from the dataset before submission to the second stage.
The second stage of the twostage approaches
where Z is the matrix of SNP marker covariates, $u~N\left(0,{I}_{p}{\sigma}_{u}^{2}\right)$, I_{ p } is the p dimensional identity matrix and ${\sigma}_{u}^{2}$ is the variance of marker effects.
where Z^{ T } is the transpose of Z. Alternatively, for computing some of the heritability measures, we also fitted model (6) with $\text{var}\left(g\right)=G={I}_{n}{\sigma}_{g}^{2}$, i.e., assuming that genotypic effects are uncorrelated for Methods 1 to 3, where ${\sigma}_{g}^{2}$ is the genetic variance and I_{ n } is the ndimensional identity matrix. In general, when fitting model 6, assuming a linear variancecovariance model for G as defined in (8) it can sometimes happen that the estimated marker variance (${\widehat{\sigma}}_{u}^{2}$) is negative, yet it should not be. To ensure that the estimated ${\widehat{\sigma}}_{u}^{2}$ is nonnegative it is necessary to specify a zero lower boundary constraint for ${\widehat{\sigma}}_{u}^{2}$. This can be accomplished using the lower b=valuelist option of the parms statement of the MIXED procedure when using the SAS system.
Simulation of datasets
Assumed field design and model
The variance components for the AgReliant real maize data set estimated by RRBLUP models assuming genotypes are correlated according to the linear variance model
Variance components  Scenario 1  Scenario 2 

Marker (${\sigma}_{u}^{2}$)  0.2019  0.2019/10 
Block (${\sigma}_{b}^{2}$)  69.9089  69.9089 
Residual (${\sigma}_{e}^{2}$)  48.6728  48.6728 
The variance components for the KWSSynbreed real maize data set estimated by RRBLUP models assuming genotypes are correlated according to the linear variance model
Variance components  Scenario 3  Scenario 4 

Marker (${\sigma}_{u}^{2}$)  0.005892  0.005892/10 
Trial (${\sigma}_{l}^{2}$)  11.8285  11.8285 
Trial×Replicate (${\sigma}_{r}^{2}$)  3.3231  3.3231 
Trial×Replicate×Block (${\sigma}_{b}^{2}$)  6.3148  6.3148 
Tester×Nongenotyped $\left({\sigma}_{{g}_{2}}^{2}\right)$ lines×GRP (${\sigma}_{g}^{2}$)  34.5717  34.5717 
Residual (${\sigma}_{e}^{2}$)  53.8715  53.8715 
Description of the real datasets and estimation of variancecomponents
We used two real datasets to get marker information and estimates of the marker, block and error variance components, which we needed to simulate the true breeding values and phenotypic data, assuming correlated genotypes (Tables 1 and 2). For Scenarios 2 and 4 we divided the marker variance for Scenarios 1 and 3 by 10, respectively, to obtain smaller estimates of heritability (Tables 1 and 2).
The AgReliant maize dataset
The first data set we used was a small dataset provided by AgReliant Genetics. It consisted of 177 doubled haploid maize lines derived from biparental crosses. The hybrid performance for kernel dry weight per plot of testcross genotypes was assessed with the same common tester using an unreplicated augmented trial design with incomplete blocks. Although the testcross genotypes were tested in six locations in one year, not all testcross genotypes were tested in each location. Furthermore, three to five incomplete blocks, each having one single row of plots, were used per location. Standard varieties connected the different blocks in the sense that they allowed estimation of the interblock variance and separation of the block from the error variance. The standard varieties themselves were not used in predicting g but were used merely to facilitate analysis of the testcross genotypes. Markers with more than 20% missing values, or more than 5% heterozygous genotypes, or with minor allele frequency less than 2.5% were discarded [10]. We used the data for only one of the six locations with the RRBLUP model to obtain variance components needed to simulate the random marker, block and plot effects for Scenarios 1 and 2. The selected location had a single unreplicated trial, 5 blocks, 2 checks and 177 lines, all of which were genotyped. Since the two checks had markers, just like all the other genotypes, they were treated in the exact same way as the other genotypes in the RRBLUP model.
where y_{ ij } is the yield of the ith genotype in the jth block, φ is the general effect or mean, b_{ j } is the random effect of the jth block, the random vector g = (g_{1}, …, g_{ n })^{ T } is modeled as in equation 7 and also has variance $\text{var}\left(g=\mathit{Zu}\right)=Z{Z}^{T}{\sigma}_{u}^{2}$. The terms Z, Z^{ T }, u and ${\sigma}_{u}^{2}$ are defined as in equations 7 and 8 whereas e_{ ij } is the residual plot error associated with y_{ ij }.
The KWSSynbreed maize dataset
Definition of the variables in the KWSSynbreed dataset used to compute covariance parameters used in the simulations for Scenarios 3 and 4
Tester  GRP  Z1  Z2  GENA  GENB  Description of GENA 

T_{0}  C_{1}C_{6}  0  0  C_{1}C_{6}  1  Hybrid checks 16 
T_{0}  nT  0  1  nT_{1} nT_{4}  1  4 lines, not genotyped, unknown tester 
T_{0}  fT  0  1  fT_{1} fT_{66}  1  16 lines, not genotyped, tested with a foreign tester 
T_{1}  G_{0}  0  1  T1_{1}T1_{66}  1  66 lines, not genotyped and tested to T1 
T_{2}  G_{0}  0  1  T2_{1}T2_{61}  1  61 lines, not genotyped and tested to T2 
T_{1}  G_{1}  1  0  1682  1682  682 lines, genotyped and tested to T1 in group G1 
T_{1}  G_{3}  1  0  683698  683698  16 lines, genotyped and tested to T1 in group G3 
Fitting a linear variance model (7 and 8) to these data requires using a variancecovariance matrix of dimension n_{1} × n_{1}, where n_{1} is the number of genotyped lines. The vector of effects of genotyped lines must therefore be of dimension n_{1}. This presents a challenge for the KWS data set because the vector of random effects of all the genotypes (g) contains both the vector of effects of the n_{1} genotyped lines (g_{1}) plus the vector of the effects of the n_{2} nongenotyped lines (g_{2}) and so has a larger dimension (n_{1}+n_{2}) than n_{1}. To facilitate fitting the linear variance model for the genotyped lines we proceed as follows. First, we create a dummy variable in our dataset (Z_{1im}, i =1,…,n_{1}, m=1,…, 11 groups) equal to one for genotyped lines and zero otherwise. Second, we create a variable called GENA in the dataset with a unique level for each of the genotyped and the nongenotyped lines. Third, we create a second variable called GENB equal to GENA for the genotyped lines but equal to the level for any one of the genotyped lines for all the nongenotyped lines. Thus, the variable GENB has n_{1} levels, corresponding to the n_{1} genotyped lines. For example in Table 3, the variable GENB, whose effect is modelled by g_{1}, has been set equal to 1, 2,…, 698 for the 698 genotyped lines and to 1, the label for the first genotyped line, for all the 202 ungenotyped lines. The genetic effect g_{1i} of the ith genotyped line will be represented in the mixed model by the term Z_{1im}g_{1i}. This term will become zero for all the records corresponding to the nongenotyped lines, because for these records we have set Z_{1im}=0. This ensures that the number of random genotypic effects to be predicted for g_{1} equals the dimension of the linear variancecovariance matrix (n_{1}). The nongenotyped lines therefore make no contribution at all to the estimated variancecovariance matrix of the genotypes. They are, in other words, switched off.
The vector of random effects for the genotyped lines g_{1} is modelled by RRBLUP as g_{1} = Zu with $\text{var}\left({g}_{1}=\mathit{Zu}\right)=Z{Z}^{T}{\sigma}_{u}^{2}$, where Z is the n_{1} × p design matrix for SNP markers for the n_{1} genotyped lines and u = (u_{1}, …, u_{ p })^{ T } is the vector of p random SNP marker effects, with $u~N\left(0,{I}_{p}{\sigma}_{u}^{2}\right)$. I_{ p } is the pdimensional identity matrix and ${\sigma}_{u}^{2}$ is the variance of SNP marker effects.
We represent the genetic effects g_{2i} of the ith nongenotyped line in a similar fashion as for g_{1i}, i.e., we use the term Z_{2im}g_{2i}, where Z_{2i} is a dummy variable that is equal to one for all the nongenotyped lines and equal to zero for all the genotyped lines. The effects g_{2i} are assumed to be independent normally and distributed with variance ${\sigma}_{{g}_{2}}^{2}$.
where y_{ ijklmn } is the response of the ith genotype in the jth block nested within the kth replicate in the lth trial in the mth group tested against the nth tester. φ is the general effect, t_{ l } is the random effect of the lth trial, assumed iid $N\left(0,{\sigma}_{t}^{2}\right)$, r_{ kl } is the random effect of the kth replicate nested within the lth trial, assumed iid $N\left(0,{\sigma}_{r}^{2}\right)$, b_{ jkl } is the random effect of the jth block nested within the kth replicate in the lth trial, assumed iid $N\left(0,{\sigma}_{b}^{2}\right)$, δ_{ m } is the fixed effect of the mth group of checks, testers and genotypes, τ_{ n } denotes the effect of the nth tester (Table 3) and e_{ ijklmn } is the residual plot error associated with y_{ ijklmn } and is assumed to be iid $N\left(0,{\sigma}_{e}^{2}\right)$, where ${\sigma}_{e}^{2}$ is the error variance.
To implement the model using the REML package PROC MIXED of the SAS System [13], the random genotypic effects were coded using the variables defined in Table 3. The random genotypic effect of the ith genotyped line in the mth group, Z_{1im}g_{1im}, was coded as (Z1*TS*GRP*GENB) using the variables tester (TS), group (GRP), genotypes (GENB), and Z1, where the last variable was specified as a quantitative variable, while the first three variables were declared as categorical variables (using the CLASS statement). The variable Z1 corresponds to the switch variable Z_{1im} in the model (11). The random effect Z_{2im}g_{2im} of the ith nongenotyped line in the mth group was coded as (Z2*TS*GRP*GENA) using the variables tester (TS), group (GRP) and genotypes (GENA) described in Table 3. Z2 is a second quantitative variable corresponding to the switch variable Z_{2im}.
Estimating predictive accuracy from predictive ability and heritability
An important question is how to estimate heritability H^{2}. The fact that the definition of $\widehat{g}$ used in ${r}_{g,\widehat{g}}$ requires a markerbased model for g suggests that the same model should be used for defining heritability H^{2}. The problem in practice is that the true model is not known, so that different methods for genomic selection (GS) are usually applied and their predictions compared empirically via CV [15]. To make any progress, some model must be chosen for defining predictive accuracy, and if the chosen model is close to the model for some GS method, then that same method would potentially be preferred for the estimation of predictive accuracy. Moreover, some methods for GS do not have an explicit underlying model. This is the case for some methods, for example, in the machine learning realm.
The difficulty in choosing a model for heritability H^{2} makes it hard to devise an unambiguous definition for H^{2}. Thus, any estimate of predictive accuracy should be taken only as a rough indication of precision. We suggest that the model underlying ridge regression BLUP be used to define heritability H^{2}. This is because this method is the most commonly used one for GS and has been shown to have good properties. It is based on a specific mixed model, so an estimate of H^{2} can be obtained in various ways [16].
Crossvalidation
Summary of the main properties of the seven methods
Method  Estimates heritability?  Requires heritability to estimate predictive accuracy?  Model for heritability assumes uncorrelated genotypes?  Model for predictive ability assumes correlated genotypes?  Requires cross validation? 

1  Yes  Yes  Yes  Yes  Yes 
2  Yes  Yes  Yes  Yes  Yes 
3  Yes  Yes  Yes  Yes  Yes 
4  Yes  Yes  Yes  Yes  Yes 
5  Yes  No      No 
6  No  No    Yes  Yes 
7  No  No      No 
Methods for estimating predictive accuracy
Descriptive statistics for the estimated true heritability for all the datasets out of a possible total of 1000 for which an estimate of heritability was available for all the five methods in each scenario
Methods  

M0  *M1(15)  M2(16)  M3(17)  M4(21)  M5(24)  
Scenario  ^{†}Statistic  ${H}_{\mathit{\text{true}}}^{2}$  ${\widehat{H}}_{\mathrm{m}1}^{2}$  ${\widehat{H}}_{m2}^{2}$  ${\widehat{H}}_{m3}^{2}$  ${\widehat{H}}_{m4}^{2}$  ${\widehat{H}}_{m5}^{2}$ 
1  ${\widehat{H}}^{2}=0$  0  0  0  0  0  0 
MIN  0.56  0.09  0.16  0.16  0.16  0.50  
MAX  0.82  0.50  0.66  0.66  0.55  0.80  
MEAN  0.71  0.32  0.48  0.48  0.34  0.67  
STD  0.04  0.06  0.08  0.08  0.06  0.05  
MSD  0.000  0.160  0.061  0.061  0.143  0.004  
2  ${\widehat{H}}^{2}=0$  0  152  152  0  0  0 
MIN  0.09  0.00  0.00  0.00  0.00  0.00  
MAX  0.73  0.30  0.46  0.46  0.28  0.63  
MEAN  0.42  0.09  0.15  0.18  0.08  0.33  
STD  0.11  0.07  0.11  0.10  0.05  0.11  
^{†}MSD  0.000  0.128  0.094  0.083  0.128  0.025  
3  ${\widehat{H}}^{2}=0$  0  0  0  0  0  0 
MIN  0.66  0.35  0.33  0.34  0.28  0.64  
MAX  0.79  0.62  0.61  0.61  0.53  0.78  
MEAN  0.73  0.51  0.49  0.50  0.40  0.72  
STD  0.02  0.04  0.04  0.04  0.03  0.02  
MSD  0.000  0.051  0.057  0.055  0.110  0.001  
4  ${\widehat{H}}^{2}=0$  0  0  0  0  0  0 
MIN  0.36  0.00  0.00  0.55  0.02  0.23  
MAX  0.63  0.32  0.31  0.31  0.15  0.52  
MEAN  0.52  0.14  0.13  0.13  0.07  0.39  
STD  0.04  0.07  0.06  0.07  0.02  0.05  
MSD  0.000  0.151  0.155  0.152  0.202  0.020 
Method 1: Standard measure
where ${\sigma}_{g}^{2}$ is the genetic variance, r is the number of replicates and σ^{2}_{ e } is the variance of plot error [12]. This estimator is valid for randomized complete block designs, but is an ad hoc approximation for incomplete block designs. Also, the estimator is not applicable with spatial methods of analysis [17].
where $\overline{\upsilon}$ is the mean variance of a difference of two adjusted genotypic means (BLUE) and ${\sigma}_{g}^{2}$ is the genetic variance estimated from (6) assuming independent genotypic effects.
where ${\overline{\upsilon}}_{{}_{\mathit{\text{BLUP}}}}$ is the mean variance of a difference of the BLUP of two genotypic effects ${\widehat{g}}_{i}$. We used the BLUP of μ_{ i } = φ + g_{ i } as the phenotypic data in the mixed model for Method 3. Further details on the computation of ${\overline{\upsilon}}_{{}_{\mathit{\text{BLUP}}}}$ and $\overline{\upsilon}$ are in Additional file 1.
Method 4: A new proposed measure for estimating heritability
where $p=\widehat{\mu}={\left({\widehat{\mu}}_{1},{\widehat{\mu}}_{2},\dots ,{\widehat{\mu}}_{n}\right)}^{T}$ is the vector of observed phenotypes. The observed phenotype ${\widehat{\mu}}_{i}$ of the ith genotype is the adjusted mean computed for this genotype for a single location.
An estimate of this is easy to compute, as is an estimate of $\left({s}_{g}^{2}\right)$, by plugging in estimates for the variancecomponents in G and R. For illustration of the new Method 4, we consider three special cases in Additional file 2.
Method 5: A new direct method for estimating ${r}_{g,\widehat{g}}$
This method uses the RRBLUP of g as the “phenotype” to compute an alternative estimator of predictive accuracy unlike that produced by the methods that require crossvalidation and use the adjusted means as the phenotypes. Heritability can be computed as the square root of the estimated predictive accuracy.
and $\widehat{\phi}={\left({1}^{T}{V}^{1}1\right)}^{1}{1}^{T}{V}^{1}p.$ Thus, BLUP(g = Zu) = GV^{ 1}Qp, where Q = I  1(1^{ T }V^{ 1}1)^{ 1}1^{ T }V^{ 1}. Or in an even more compact form $\mathit{\text{BLUP}}\left(g=\mathit{Zu}\right)=\widehat{g}=\mathit{Cp}$ with C = GV^{ 1}Q.
Descriptive statistics for predictive accuracy (estimates less than 0 were set to 0 whereas estimates greater than 1 were set to 1) by scenario
Methods  

Scenario  ^{†}Statistic  M0  ^{*}M1(15)  M2(16)  M3(17)  M4(21)  M5(24)  M6(25)  M7(35) 
${r}_{g,\widehat{g}}$  $\frac{{r}_{\widehat{g},p}}{{\widehat{H}}_{\mathrm{m}1}}$  $\frac{{r}_{\widehat{g},p}}{{\widehat{H}}_{m2}}$  $\frac{{r}_{\widehat{g},p}}{{\widehat{H}}_{m3}}$  $\frac{{r}_{\widehat{g},p}}{{\widehat{H}}_{m4}}$  ${\widehat{H}}_{m5}$  ${r}_{g,\widehat{g},m6}$  ${\widehat{\rho}}_{m7}$  
1  N  1000  1000  1000  1000  1000  1000  1000  1000 
MIN  0.750  0.327  0.265  0.265  0.384  0.707  0.316  0.750  
MEAN  0.843^{c}  0.877^{a}  0.727 ^{e}  0.727^{e}  0.858^{b}  0.819^{d}  0.663^{f}  0.840^{c}  
MAX  0.908  1.000  1.000  1.000  1.000  0.893  0.884  0.899  
STD  0.024  0.109  0.104  0.104  0.093  0.028  0.084  0.023  
MSD  0.000  0.013  0.025  0.025  0.009  0.002  0.040  0.001  
Q1  0.829  0.807  0.661  0.661  0.802  0.803  0.612  0.826  
Median  0.846  0.890  0.723  0.724  0.862  0.822  0.665  0.841  
Q3  0.860  0.983  0.793  0.793  0.923  0.839  0.716  0.856  
2  N  839  839  839  839  839  839  839  839 
MIN  0.31  0.00  0.00  0.00  0.00  0.06  0.00  0.08  
MEAN  0.65^{a}  0.63^{c}  0.50^{e}  0.50^{e}  0.64^{ab}  0.58^{d}  0.46^{f}  0.64^{bc}  
MAX  0.85  1.00  1.00  1.00  1.00  0.79  1.00  0.82  
STD  0.09  0.29  0.26  0.26  0.26  0.10  0.20  0.09  
MSD  0.000  0.083  0.092  0.092  0.069  0.02  0.081  0.011  
Q1  0.61  0.42  0.31  0.31  0.47  0.53  0.33  0.59  
Median  0.66  0.64  0.48  0.48  0.68  0.59  0.47  0.65  
Q3  0.71  0.91  0.67  0.67  0.85  0.64  0.59  0.70  
3  N  1000  1000  1000  1000  1000  1000  1000  1000 
MIN  0.81  0.60  0.61  0.61  0.69  0.80  0.54  0.78  
MEAN  0.85^{a}  0.72^{c}  0.73^{c}  0.73^{c}  0.81^{b}  0.85^{a}  0.64^{d}  0.81^{b}  
MAX  0.89  0.88  0.90  0.89  0.96  0.88  0.78  0.84  
STD  0.01  0.04  0.04  0.04  0.04  0.01  0.04  0.01  
MSD  0.0000  0.0193  0.0169  0.0176  0.0036  0.0002  0.0477  0.0017  
Q1  0.85  0.69  0.70  0.70  0.79  0.84  0.61  0.81  
Median  0.85  0.72  0.73  0.73  0.81  0.85  0.64  0.81  
Q3  0.86  0.75  0.76  0.76  0.84  0.85  0.66  0.82  
4  N  955  955  955  955  955  955  955  955 
MIN  0.60  0.14  0.14  0.14  0.15  0.48  0.24  0.52  
MEAN  0.72^{a}  0.32^{e}  0.33^{e}  0.33^{e}  0.36^{d}  0.62^{c}  0.63^{b}  0.64^{b}  
MAX  0.79  0.52  0.53  0.52  0.56  0.72  0.93  0.72  
STD  0.03  0.06  0.06  0.06  0.07  0.04  0.09  0.03  
MSD  0.000  0.160  0.157  0.158  0.130  0.012  0.015  0.007  
Q1  0.70  0.29  0.29  0.29  0.32  0.60  0.57  0.62  
Median  0.72  0.32  0.33  0.33  0.37  0.62  0.64  0.64  
Q3  0.74  0.36  0.37  0.37  0.41  0.65  0.70  0.66 
Method 7: This method is commonly used in animal breeding [20–22]
and the accuracy by its square root, where n is the total number of genotypes in the data set. The SAS (version 9.3) code used to simulate the phenotypic data and fit all the seven models is provided in Additional file 4.
Evaluation of simulated data
We used the twostage analysis and the methods described above to estimate the correlations between the predicted and the true breeding values ${r}_{g,\widehat{g}}$. We computed the true heritability as the square of the correlation between the predicted and the true breeding values and estimated heritability using the five different approaches. We then computed the ratio of the expected value of the genetic variance to the expected value of the phenotypic variance and used this to compute heritability based on the new proposed method (Method 4) for estimating heritability. Moreover, we estimated the adjusted least square means of genotypes from the first stage using simulated data. The adjusted least square means were used in the second stage in crossvalidations as the phenotypic data. Also, the variancecovariance matrix of the adjusted means was used to compute an ad hoc measure of heritability according to equation 16. Because the KWS maize dataset had many genotypes (n = 698) the mixed models were computationally very demanding to fit. So, for example, the slowest method, Method 6, took only 17.5 hrs to fit all the 1000 small data sets in one scenario in SAS Version 9.3 running on a 64bit Windows 7 workstation with 8 GB RAM and an Intel Core Quad 2.66, but it took 192 hrs to fit the same model to 1000 large data sets. Hence, we first estimated the start values for the variancecomponents of the mixed models using the hpmixed procedure of SAS to enhance computational efficiency.
Comparing heritabilities
where N is the total number of the simulated datasets and j= (1, 2, …, N) denotes the jth simulated data set. Moreover, we computed descriptive statistics for the true and estimated heritabilities.
Comparing predictive accuracies
For each scenario we compared the simulated true and the estimated predictive accuracies for the seven methods using ttests (α = 5%) adjusted for multiplicity using simulation adjustment. The ttests were derived from a mixed model with fixed effects for method and scenario and their interaction and a random effect for simulation replicates nested within scenarios [6].
Results
Heritability
Heritability was estimated by Methods 1 to 5 only. The estimated heritability was closer to its true simulated value for Methods 2, 3 and 5 than for Methods 1 and 4 in terms of its minimum, maximum, mean, standard deviation and mean squared deviation for all the four scenarios. All the five methods (Methods 1 to 5) underestimate the minimum, maximum and the mean true heritability in all the scenarios. Method 5 produced estimates closest to the true heritability for all the four scenarios. Across scenarios based on the same data set, the estimated heritability tended to be closer to its true value in Scenario 1 than in 2 and in Scenario 3 than in 4 (Table 5), implying that reducing the genetic variance by a factor of 10 in scenarios 2 and 4 reduced the accuracy of estimated heritability.
Predictive accuracy
In general, all the seven methods produced reasonable estimates of predictive accuracy across all the four scenarios. The estimated predictive accuracy was more precise for Scenarios 3 and 4, based on the large dataset, than for Scenarios 1 and 2, for all the seven methods (Table 6, Figures 1, 2 and 3). Reducing the genetic variance by a factor of 10 while leaving all the other variance components unchanged degrades the precision of the estimated predictive accuracy more for the smaller of the two datasets (Table 6, Figures 1, 2 and 3 and Additional file 3: Figures S1S4). Methods 5 and 7 were the best overall and gave the least biased and most precise estimates of predictive accuracy, most notably for Scenarios 1, 3 and 4 (Table 6 and Figures 1, 2 and 3). Even so, Method 5 tended to be more precise than Method 7 for both the scenarios (3 and 4) based on the larger dataset. All estimates of predictive accuracy for Methods 5 and 7 were between 0 and 1 for all scenarios. Also, the models for Methods 5 and 7 converged for all the 1000 simulated datasets in all the scenarios (Tables 5 and 6, Additional file 3: Figures S1S2). Unlike Methods 5 and 7, the performances of the other methods were more varied across scenarios. In particular, there was a greater tendency for the estimated predictive accuracy to exceed one (“overshooting”) or to be smaller than zero (“undershooting”) and a higher frequency of failure of the algorithms used to fit the RRBLUP models to converge (Additional file 3: Table S1, Additional file 3: Figures S1S8).
For Scenario 1 overshooting was most frequent and severe (greater in magnitude) for Method 1 (21.8%, n=1000, range 1.00041.8960) followed by Methods 4 (6.8%, range 1.00151.1917), 2 (1.5%, range 1.00221.4152) and 3 (1.5%, range 1.00181.4153). In contrast, all estimates of predictive accuracy for Methods 5, 6 and 7 fell between 0 and 1. Moreover, all the seven models converged for all the 1000 simulated datasets (Table 6 and Additional file 3: Table S1).
Compared to Scenario 1, overshooting and undershooting were more common for Methods 1, 2, 3, 4 and 6 in Scenario 2. Generally, overshooting was more serious (greater in absolute magnitude) than undershooting, particularly for Methods 1 (n=164 datasets), 2 (n=65), 3 (n=65) and 4 (n=113) (Table 6, Additional file 3: Figures S1, S4 and S6). The problem of overshooting or undershooting did not occur for any method in Scenario 3. Although the problem of overshooting still persisted for Methods 1 (n=95), 2 (n=104), 3 (n=87) and 4 (n=163) in Scenario 4, these methods had three further drawbacks in Scenario 4. The first was the breakdown of the method for computing predictive accuracy because estimated heritability was zero, most especially for Methods 1 (n=27) and 2 (n=27). The second was that the genetic variance estimate was zero for Method 3 (n=27). The third was the failure of the mixed model used to compute predictive ability required by Methods 1, 2, 3, 4 and 6 to converge (n=18). As a result, predictive accuracy could not be computed for 45 datasets for each of the Methods 1, 2 and 3 in Scenario 4. Undershooting was rather rare by comparison and was noted only for Method 3 (n=17) in Scenario 4 (Additional file 3: Figures S2, S4 and S8). Aside from overshooting and undershooting, deviation of the predictive accuracy from its expected values was also caused by overestimation and underestimation. Considering only the values of predictive accuracy between 0 and 1, the seven methods tended to underestimate the true accuracy across all the four scenarios. Underestimation tended to be more severe for Methods 1, 2, 3, 4 and 6 than Methods 5 and 7. This was most evident in Scenario 4. By comparison, overestimation was far less common (Table 6, Figures 2 and 3, Additional file 3: Figure S2S4).
For 11 datasets from Scenario 2 the estimated true accuracy was smaller than zero because the estimated variances of the BLUPs were zero and the estimated genetic variances were nearly zero. We expect plant breeders to discard genotypes for which the estimated genetic variance is nearly zero in making selection decisions in real applications. Consequently, we excluded the 11 simulated datasets with negative true accuracies from all the comparisons to mimic what plant breeders do in practice. There was therefore no estimated true accuracy to compare with the corresponding estimated predictive accuracy for all the seven methods. Similarly excluded from all the comparisons were four further datasets in Scenario 2 for which the mixed models for estimating the true accuracy did not converge.
Correlation between predictive accuracies (estimates less than 0 were set to 0 whereas estimates greater than 1 were set to 1) for pairs of the seven methods by scenario
Scenario  Method  M1  M2  M3  M4  M5  M6  M7 

1  M1  1.00  
M2  0.94  1.00  
M3  0.94  1.00  1.00  
M4  0.90  0.89  0.89  1.00  
M5  0.02  0.04  0.04  0.18  1.00  
M6  0.81  0.84  0.84  0.96  0.06  1.00  
M7  0.02  0.04  0.04  0.18  1.00  0.07  1.00  
2  M1  1.00  
M2  0.97  1.00  
M3  0.97  1.00  1.00  
M4  0.82  0.78  0.78  1.00  
M5  0.21  0.17  0.17  0.04  1.00  
M6  0.70  0.67  0.67  0.91  0.02  1.00  
M7  0.26  0.22  0.22  0.11  0.95  0.03  1.00  
3  M1  1.00  
M2  1.00  1.00  
M3  1.00  1.00  1.00  
M4  0.91  0.91  0.91  1.00  
M5  0.11  0.12  0.12  0.32  1.00  
M6  0.83  0.83  0.83  0.98  0.28  1.00  
M7  0.11  0.12  0.12  0.32  1.00  0.28  1.00  
4  M1  1.00  
M2  1.00  1.00  
M3  1.00  1.00  1.00  
M4  0.99  0.99  0.99  1.00  
M5  0.59  0.59  0.59  0.58  1.00  
M6  0.77  0.77  0.77  0.79  0.04  1.00  
M7  0.59  0.59  0.59  0.58  1.00  0.05  1.00 
Discussion
Heritability
One possible definition of heritability [27] is based on the squared correlation between “genotype” and “phenotype”. In our current work, we use various ad hoc measures of heritability. The one proposed by [18] assesses the squared correlations between BLUPs of genotypic values and the true genotypic values using Method 3. Another measure, proposed by [16], considers the correlation between adjusted means (BLUEs of genotypic values) and the true genotypic values using Method 2. So, one may argue that these different measures use different definitions of “the phenotype”.
In this paper, we use estimates of heritability to compute “predictive accuracy” as ${r}_{\widehat{g},p}/H$, where ${r}_{\widehat{g},p}$ is the correlation between genomic selection estimators of the true breeding values g and the “phenotypic values” in the validation set and H is the square root of heritability. In this application, the “phenotypes” are adjusted means (BLUEs), so estimators of the square root of heritability H that take BLUEs to be the phenotype are appropriate.
It is important to note that ${r}_{\widehat{g},p}/H$ is itself an estimator of the square root of heritability if we take the RRBLUPs as the “phenotypes”. An important property of the procedures we consider (this provides estimators of H by taking RRBLUPs to be the phenotypes) is that ${r}_{\widehat{g},p}$ is obtained from crossvalidation. Alternatively, we also estimate heritability H^{2} (or H) without crossvalidation using similar ideas to those used for the ad hoc measures of heritability H^{2} and for the “direct method” (Method 5). The quantity ${H}_{m5}^{2}$ (24) provides an alternative estimator of heritability when the RRBLUP of the genetic variance (g) is considered as the “phenotype”. This estimator (${H}_{m5}^{2}$) was the most accurate of the five we used to compute heritability. But in our crossvalidations, the phenotypes are always the adjusted means. So, we just use (24) as an alternative estimator of predictive accuracy.
The strikingly poor performances of Methods 1 to 3 as indicated by all the estimated mean heritabilities falling below the minimum of the true heritability may seem surprising at first sight but in the case of Methods 1 to 3 may reflect the fact that these three methods assume that genotypes are uncorrelated. If this is true then we would expect the performance of these methods to improve considerably if the true heritability used as the benchmark were also estimated using a model that assumes uncorrelated genotypes. To test this expectation, we recalculated the true heritability assuming that the genotypes are uncorrelated for each of the four scenarios by setting all the covariances in the variancecovariance matrix of genotypes to zero. Using the new benchmark led, as expected, to a much better agreement between the new true heritability and its estimates by Methods 1 to 3 (Additional file 3: Table S2). This demonstrates compellingly that Methods 1 to 3 are all reasonably good at estimating heritability when genotypes are not correlated but are severely biased downwards when they are. The downward bias implies, furthermore, that Methods 1 to 3 are not suited for estimating heritability used to divide predictive ability to obtain predictive accuracy in genomic prediction for which genotypes are typically assumed to be correlated. By contrast, Method 5 that assumes correlated genotypes performs much better at estimating heritability even though the estimated heritability is merely a byproduct and not needed for estimating predictive accuracy.
Method 4 differs from Methods 1 to 3 in assuming that the genotypes are correlated, unlike the latter methods that assume that genotypes are independent. This suggest that there must be yet another reason that the estimated mean heritability for Method 4 falls below the minimum expected true heritability estimated assuming that the genotypes are correlated. We can think of two plausible explanations for this discrepancy both of which apply equally to all Methods 1 to 4. The first is that all the heritability estimators for Methods 1 to 4 are constructed as ratios of the genetic and the phenotypic variances such that the greater is the phenotypic variance the smaller is the estimated heritability, whereas we defined the true heritability in terms of the squared correlation between true and estimated genotypic effect. The second relates to the observation that despite its poor estimates of heritability relative to those for Methods 1 to 3, the estimated predictive accuracy for Method 4 is generally closer to the estimated true accuracy than the estimates for Methods 1 to 3. This is quite intriguing because Methods 1 to 4 calculate predictive accuracy as the ratio of predictive ability to heritability. Since all the four methods use the exact same values of predictive ability and since Method 4 yields somewhat poorer estimates of heritability than Methods 1 to 3, we would not logically expect Method 4 to produce better estimates of predictive accuracy. That it actually did suggests that the reliability of approximating predictive accuracy by dividing predictive ability by the square root of heritability is questionable, at the very least for the specific configurations of the phenotypic and genotypic variances we used in our simulation scenarios.
Predictive accuracy
We compared the performances of seven methods for estimating predictive accuracy in genomic selection using 1000 datasets simulated according to an alphadesign for each of four scenarios based on genetic and residual variance estimates calculated from two real datasets. The results show that, of the seven methods, a new proposed method (Method 5) and a method which is well established in animal breeding programs (Method 7, [18]), consistently gave the least biased, most precise and stable estimates of predictive accuracy across all the four scenarios. Method 5 was at least as good as or better than Method 7 for estimating predictive accuracy. The other methods performed somewhat inconsistently across scenarios and suffered varying degrees of overshooting, undershooting and convergence problems. All the methods were more likely to underestimate than overestimate the true predictive accuracy when only datasets for which the estimated predictive accuracies fell between 0 and 1 were considered. The 0–1 truncation of the estimated predictive accuracy reflects the fact that we should not use the ratio of predictive ability to heritability (${r}_{\widehat{g},p}/H$) in practice if it does not fall within the interval [0, 1].
In summary, Methods 5 and 7 had the best performance followed by Method 4. Method 6 was the third best whereas Methods 1, 2 and 3 had rather similar and the worst performance. Methods 5 and 7 had rather similar performance in all scenarios despite the theoretical expectation that Method 5 should do better than Method 7 for the scenarios with small sample size. This expectation arises from the fact that whereas Method 7 assumes that the focal genotypes are derived from an infinite target population, Method 5 assumes that the sampled genotypes arise from a finite population. Consequently, the two methods may be expected to perform well for large sample sizes and Method 5 to perform better than Method 7 in small sample situations. The similar performance of Methods 5 and 7 is therefore tentative and its generality will be explored for a wider range of sample sizes in a sequel to this paper focusing on the influence of sample size on the predictive performance of the seven methods.
Although their empirical performances in the simulations were often reasonable, Methods 1, 2 and 3 involve dividing two quantities computed using two different models with conflicting assumptions. Specifically, they involve dividing predictive ability computed from an RRBLUP model, assuming that genotypes are correlated, by the square root of heritability computed from a model assuming that genotypes are uncorrelated. The computation of predictive ability using the model assuming that the genotypes are correlated, when heritability is computed assuming uncorrelated genotypes, would seem unavoidable when using RRBLUP. This is because genomic breeding values cannot be predicted using RRBLUP if the genotypes are assumed to be independent. This theoretical inconsistency undermined the performance of these three methods in several instances when the genetic variance estimated assuming uncorrelated genotypes was zero or nearly zero. This rendered predictive accuracy inestimable for Methods 1, 2 and 3 in these cases.
Despite the inferior performance of Methods 1 to 3, linked to the inconsistency in the definitions of their numerators and denominators, relative to the methods that estimate predictive accuracy directly, this theoretical inconsistency has not deterred plant breeders from using these approaches. In fact, Methods 1 to 3 are the most frequently used by plant breeders. These three methods are not very similar by construction, despite the similarity of their performance. Hence, the similar performance could not necessarily have been anticipated a priori. Accordingly, by studying the properties of these methods alongside those of the other contending methods, we have ascertained whether and when their theoretical inconsistency may lead to inferior performance. Our findings suggest that these methods should be used with care, especially when the genetic variance is very small, so that predictive accuracy is likely to be either inestimable or overestimated.
Although rare and probably relatively simple, there are instances in which the theoretical inconsistency is immaterial. For example, an independent model can be obtained in such simple special cases as a doubled haploid population, resulting from a single cross [2], if the dependent model is a conditional model that considers genetic variancecovariance conditioning on the marker genotypes whereas the marker genotypes are taken as random variables. In complex pedigrees, however, the unconditional model will also involve correlations, so that the impact of the theoretical inconsistency is more likely to be consequential.
We emphasize also that while our simulation results hold for the RRBLUP model, their applicability to other models than RRBLUP remains to be investigated.
Influence of the size of genetic variance
The size of the estimated genetic variance and hence heritability exerted the strongest influence on the variation in estimates of predictive accuracy. The estimated predictive accuracy was closer to its true value for all the methods in Scenarios 1 and 3 than in Scenarios 2 and 4 for all the 1000 datasets, because the simulated genetic variances for Scenarios 1 and 3 were 10 times larger than those for Scenarios 2 and 4. When the simulated genetic variance was small (Scenarios 2 and 4), there was a higher likelihood of obtaining extremely high values of estimated genetic variances than when a higher genetic variance was simulated (Scenarios 1 and 3). Methods 1, 2 and 3 were the most sensitive to variation in the estimated genetic variance because they all divide predictive ability by the square root of heritability to obtain predictive accuracy and hence break down when genetic variance estimate is zero, since the estimated heritability is then also zero. For Method 3, in particular, predictive accuracy becomes infinitely large when the estimated genetic variance is zero and extremely large when this variance is very small. Since Method 4 also computes predictive accuracy in the same way as Methods 1, 2 and 3 do, it also breaks down when the estimated genetic variance and hence estimated heritability is zero.
Influence of the number of genotypes
Increasing the number of genotypes, for example from 177 for Scenarios 1 and 2, to 698 for Scenarios 3 and 4, increased the time required to compute predictive accuracy by all the seven methods from a few minutes to several days, most notably for the methods that require crossvalidation (Methods 1, 2, 3, 4 and 6).
Simplicity of implementation of methods
Methods 1, 2, 3, 4 and 6 that use crossvalidation are computationally much more intensive to implement than Methods 5 and 7 that do not involve crossvalidation. As a result, Methods 5 and 7 are the simplest and computationally most efficient to implement of the seven methods. This argues for their routine use in assessing predictive accuracy in genomic selection studies.
Considering only estimated correlations between zero and one, Methods 4 and 6 gave the best estimates of predictive accuracy among the five methods that use crossvalidation, followed by Methods 3, 2 and 1, in that order.
Design considerations
We considered a single trial laid out as an alphadesign in a single location for simplicity. Hence, a more extensive simulation with more trials, locations and trial designs would be required to establish the generality of our results. Further, we considered only two data sets with different numbers of genotypes (177 and 698) and markers (275 and 11646). However, variation in the number of genotypes and markers probably also affects the estimated predictive accuracy and thus also merit further investigation. Some breeders compute heritability using methods assuming that the datasets are balanced and that the genotypes are independent. Four of the seven methods (Methods 4, 5, 6 and 7) relax these restrictive assumptions by allowing for both balanced and unbalanced datasets as well as for independent and correlated genotypes.
Conclusions
Methods 5 and 7 were the most computationally efficient to implement and gave consistently the most accurate, robust and stable estimates of predictive accuracy of the seven methods across all the four scenarios. These properties argue for their routine use in assessing predictive accuracy in genomic selection studies. Among the five methods that use crossvalidation, Methods 4 and 6 performed better than Methods 1, 2 and 3 but were clearly inferior to Methods 5 and 7. Both the genetic variance and the number of genotypes exerted strong influences on predictive accuracy. Thus, predictive accuracy was higher for the larger data set. Furthermore, reducing the genetic variance degraded predictive accuracy much more for the smaller of the two data sets. We are investigating the influences of genetic variance and the number of genotypes on predictive accuracy in genomic selection in greater detail in a sequel to this paper.
Abbreviations
 GS:

Genomic selection
 RRBLUP:

Ridgeregression BLUP
 BLUE:

Best linear unbiased estimation
 BLUP:

Best linear unbiased prediction
 REML:

Restricted maximum likelihood
 SNP:

Single nucleotide polymorphism
 CV:

Crossvalidation
 H2:

Heritability
 MME:

Mixed model equations
 p:

the BLUE of genotype means (“phenotypes”)
 S:

Sample standard deviation
 ${s}_{g}^{2}$ :

Sample variance of the true genetic breeding values g
 ${s}_{\widehat{g}}^{2}$ :

Sample variance of the predicted breeding value
 ${s}_{p}^{2}$ :

Phenotypic sample variance
 σ:

Population standard deviation
 ${\sigma}_{g}^{2}$ :

Population variance of the true genetic breeding values g
 r:

Sample correlation
 ${r}_{g,\widehat{g}}$ :

Sample correlation between the true and the predicted breeding values
 ${r}_{\widehat{g},p}$ :

Sample correlation between the BLUP of g and the observed “phenotypes” p
 ρ:

Population correlation
 ρg:

p: Population correlation between the true genetic breeding values g and the observed “phenotypes”p
 ${s}_{g,\widehat{g}}$ :

Sample covariance between the true and predicted breeding values.
Declarations
Acknowledgements
We thank AgReliant and KWS for providing the datasets used in this study. We are grateful to two anonymous reviewers for suggestions that helped improve an earlier draft of this paper. This research was funded by KWS SAAT AG, AgReliant Genetics and the German Federal Ministry of Education and Research (Bonn, Germany) within the AgroClusterEr “SynbreedSynergistic plant and animal breeding” (Grant ID: 0315526).
Authors’ Affiliations
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