 Methodology Article
 Open Access
Tilting the lasso by knowledgebased postprocessing
 Kukatharmini Tharmaratnam^{1},
 Matthew Sperrin^{2}Email authorView ORCID ID profile,
 Thomas Jaki^{1},
 Sjur Reppe^{3, 4, 5} and
 Arnoldo Frigessi^{6}
https://doi.org/10.1186/s1285901612107
© The Author(s) 2016
 Received: 7 November 2015
 Accepted: 25 August 2016
 Published: 2 September 2016
Abstract
Background
It is useful to incorporate biological knowledge on the role of genetic determinants in predicting an outcome. It is, however, not always feasible to fully elicit this information when the number of determinants is large. We present an approach to overcome this difficulty. First, using half of the available data, a shortlist of potentially interesting determinants are generated. Second, binary indications of biological importance are elicited for this much smaller number of determinants. Third, an analysis is carried out on this shortlist using the second half of the data.
Results
We show through simulations that, compared with adaptive lasso, this approach leads to models containing more biologically relevant variables, while the prediction mean squared error (PMSE) is comparable or even reduced. We also apply our approach to bone mineral density data, and again final models contain more biologically relevant variables and have reduced PMSEs.
Conclusion
Our method leads to comparable or improved predictive performance, and models with greater face validity and interpretability with feasible incorporation of biological knowledge into predictive models.
Keywords
 Bone mineral density
 Elicitation
 Lasso
Background
In medicine and genetics it is common to have a large number of covariates available to predict a response. Prior information concerning the relevance of each covariate in predicting the response may also be available. The response could be, for example, bone mineral density (BMD), and the covariates are expression levels of 20,000 genes, measured in 100 independent samples. Other examples include disease subtyping, as in breast cancer where the aim is to predict the type of disease (by multinomial regression say) based on gene expressions. There are two challenges when modelling such data. First, the number of covariates, P, is often much larger than the number of samples, n. Second, it may not be feasible, or practical, to elicit prior information concerning such a large number of covariates, P.
The first challenge, dealing with P>n, has been thoroughly studied, particularly over the last two decades. When fitting regression models, instability and overfitting problems can be mitigated using regularization methods, which shrink the coefficients of the regression model towards zero; the extent of shrinkage is controlled by a regularization parameter, which is commonly chosen to minimize the outofsample prediction error.
One commonly studied regularization method is the lasso [1], which adds a L _{1} penalty to the likelihood that relates the predictors to the response. The regularization parameter is typically chosen by cross validation. The lasso has the appealing property that it induces sparseness: in the selected model, generally only a small number of covariates have a nonzero coefficient. In many fields, such as genetics, it is reasonable to believe that this corresponds to reality — with only a small subset of the available genetic markers being needed to predict a phenotype. Accurate recovery of a subset of relevant independent predictors is of interest both to understand underlying aetiological processes, and to produce a predictive model that is transparent, has face validity and has good generalizability.
There are results describing the settings in which the lasso can recover the correct covariates, and ignore the incorrect ones [2–4]. However, these results are asymptotic, consequently this property is not guaranteed in finite samples, and place strong restrictions on the covariate design matrix — typically related to ensuring that the covariates are not too highly correlated with each other and that the signal (in terms of the absolute value of the regression coefficients of the true variables) strongly exceeds the noise, i.e. the absolute value of the coefficients of the nuisance variables. In practice, sample sizes are small, covariates are highly correlated, and signal to noise ratios may be low, so we cannot expect to recover the correct set of covariates with a naive use of lasso.
Various extensions of lasso have therefore been proposed that partially address these issues. For example, adaptive lasso [3] allows the L _{1} penalty to apply unequally to different coefficients, and in doing so has improved performance compared with lasso in recovering the correct predictors. The elastic net [5] tends to include clusters of correlated variables, whereas lasso would typically include a single representative, so elastic net has better sensitivity for detecting relevant predictors, at the expense of poorer specificity. Besides the different approaches to select relevant covariates, a number of different ideas have been presented that allow the relevance of the selected covariates to be inferred [6–8].
The second challenge, feasibly eliciting prior information for a large number of covariates, is the primary focus of this paper. In genetics, for example, many genes are already believed or known to play important roles in the underlying mechanistic processes related to a phenotypic outcome. The generality and reliability of such understanding varies, with certain genes clearly playing a strong role in diseases (like P53 in cancer, e.g [9]), but the role of other genes being more hypothetical. Biologists and clinicians would be rightly skeptical of the value of a predictive model, if none of the well understood traitrelevant genes were present. Therefore, a balance must be struck between the face validity and generalizability of the model, through inclusion of a prior that favours traitrelevant genes. In principle, this can be achieved in a Bayesian framework, which favours data with prior biological knowledge. This can be combined with the lasso using Bayesian lasso [10], or the weighted lasso [11].
However, to use a Bayesian approach, an expert such as a geneticist or biologist would be required to produce a prior distribution over a large number of variables (in excess of 1000 variables, even after prescreening). This is infeasible both because of the size of the task, and mostly because of the difficulty of formalizing prior knowledge for predicting a specific trait, based on knowledge about molecular processes known to influence related traits. For example, a limited number of genes are known to play a role in bone formation, and variation in bone mineral density (BMD) but it is likely that many so far unrecognized genes are also important for BMD. Therefore, construction of appropriate informative priors could be guided by also having some information available about the predictive ability of the genes for the outcome under consideration.
In this paper, we present an approach that allows biological expectations on the role of a reasonable number of genes in prediction of a specific outcome to be elicited, and incorporated into a model, in a manageable and coherent manner. This is made possible through a twostage approach. In the first step, we use the data only to determine, by crossvalidation guided adaptive lasso, the optimal set for prediction of the phenotype. For each gene in the adaptive lasso set, we derive a further set of genes (denoted a bag of genes) that could take the place of the gene in the adaptive lasso set with minimal loss in predictive power. The union over all bags of genes, which will be substantially smaller than the initial longlist of genes, is then taken forward. Biologists are then asked to assess the biological importance for each gene in the bag union.
This knowledge can be expressed in various ways, including full ranking of all genes in each bag, in terms of expected biological relevance. To simplify, we assume here that genes are simply classified as biologically relevant or not for the trait under investigation. A gene in the lasso set can then be switched with a biologically relevant gene present in its bag. The final model is fitted using separate data to the first step. This method allows us to find gene sets with predictive power, which have been derived from relevant data sets, but incorporating biological knowledge in a feasible manner. We show through simulations that this contributes to robust prediction signatures.
Methods
where Y _{ i } is a response variable (centered to have zero mean) measured in sample i, X _{ ij } is the j ^{ t h } covariate measured in sample i (centered to have zero mean, and scaled to have unit variance), i=1,…,n and j=1,…,P with potentially P≫n. Here, we used centered mean and unit variance for easy to interpret the regression models. The response may be a continuous phenotype and the covariates may be genes.
We wish to build a sparse model that incorporates biological information on the relevance of the covariates, to produce a final model with a relevant aetiological interpretation. We do so via a twostage approach. First the data are split into three portions: \(\mathcal {D}_{1} = \left \{\left (Y_{i},X_{i1},\ldots,X_{iP}\right)\!;~\! i\,=\,1,\ldots,m\right \}\), \(\mathcal {D}_{2} = \left \{(Y_{i},X_{i1},\ldots,X_{iP}); i = m+1, \ldots, 2m\right \}\) and \(\mathcal {D}_{3} = \left \{(Y_{i},X_{i1},\ldots,X_{iP}); i = 2m+1, \ldots, n\right \}\) where m=n/3 is our default choice. Stage one of the approach uses \(\mathcal {D}_{1}\) to produce a shortlist of covariates that are potential members of the final sparse model; we then elicit for each of these covariates whether it is biologically relevant or not. Stage two uses \(\mathcal {D}_{2}\) to fit the final sparse model, incorporating this relevance information. The final third (\(\mathcal {D}_{3}\)) is only necessary in our simulation experiments, where it is used for validation of the model derived in the second stage. In real applications the data can be divided into two portions.
Bags of biologically relevant variables
which is the usual least squares minimisation plus an L _{1} penalty on the βs, where λ is the tuning parameter denoting the severity of the penalty. An equivalent formulation is also available for generalised linear models and Cox proportional hazard models. All of these can be solved efficiently using the glmnet package in R [12].
where the weight vector w comprises the reciprocal absolute values of the ordinary least squares coefficients. This modification means the adaptive lasso consistently estimates variables, while the original lasso does not [3].
The first step of the proposed approach is to fit an adaptive lasso model, using data \(\mathcal {D}_{1}\), to select a list of covariates, denoted by S, where kfold cross validation is used to determine the penalty λ.

Bag type 1 (B1):
For each j∈S, compute the correlation Corr(X _{ j },X _{ k }) for all other covariates k≠j. Take the q covariates that are correlated with each selected covariate from adaptive lasso most. This produces a bag of alternative covariates for each gene in the adaptive lasso set.

Bag type 2 (B2):
Instead of using a fixed bag size, define a threshold on the correlation and select covariate X _{ j } if its correlation exceeds this threshold; e.g. select covariate X _{ k } if Corr(X _{ j },X _{ k })≥0.25.

Bag type 3 (B3):
For each j∈S, compute the mean squared error (MSE) when replacing X _{ j } with X _{ k }, for each j≠k, using ordinary least squares in the regression with S covariates. Usually S<n. Take the q covariates with the smallest MSE.

If there is just one biologically relevant covariate in the bag, then we switch it with the corresponding covariate selected by adaptive lasso.

If we find more than one biologically relevant covariate in the same bag, we need to select which one to switch with the corresponding originally selected one. For bag of type B1 and type B2 we chose the biologically relevant covariate which has the largest correlation with the one selected by adaptive lasso. For bag of type B3 we chose the covariate which leads to the small prediction mean square error when switched with the one selected by adaptive lasso.

If the lasso selects a biologically relevant variable, it is kept.

If there are no biologically relevant covariates in the bag, then the original covariate from the adaptive lasso solution is retained.
In bag type B3, if for a bag variable the MSE ratio (MSE of replaced model/MSE of adaptive lasso model) is less than one, then introducing that variable is particularly appealing because this leads to a reduction in the MSE of the model. Note that should a biologically relevant variable be selected into the model from two or more bags, it will appear only once in the final model (thus leading to a sparser final model).
For comparison, we also present results using the standard lasso in the first step. All fitting is carried out efficiently using the glmnet package in R [12].
Results
Simulation experiments
where ε _{ i }∼N(0,σ ^{2}), with σ ^{2} chosen to achieve a range of signal to noise ratios (SNR). Different β _{ j } values are also chosen, across different simulation settings. Additional biologically relevant covariates x _{ j },j=21,…,60, were generated with varying levels of correlation with the true covariates x _{ j },j=1,…,20. The true covariates are themselves considered biologically relevant. The remaining covariates x _{ j },j=61,…,1000 are considered not biologically relevant and are generated independently. In other words, we have a total of 60 biologically relevant variables. Of these, 20 were used in generating model. The remaining biologically relevant variables can therefore be considered to have zero β values.
We split the data into three sets each of size 100: the ‘first stage’ set \(\mathcal {D}_{1}\), the ‘second stage’ set \(\mathcal {D}_{2}\), and the validation set \(\mathcal {D}_{3}\). We used 5fold cross validation to select the penalty parameter in the lasso using data set \(\mathcal {D}_{1}\). Bag types B1 and B3 were fixed to have size q=20; we used the correlation threshold 0.25 for bag type B2. We did 100 simulation runs for each experiment, that means we simulated 100 data sets using our simulation process and split into three parts \(\mathcal {D}_{1}\), \(\mathcal {D}_{2}\) and \(\mathcal {D}_{3}\) for each such data set. We compared the performance by computing the prediction mean squared error (PMSE) in the independent dataset \(\mathcal {D}_{3}\) for the derived models.
Correlation structure for simulation study 1
Covariates in true model  Biologically relevant variables  Correlation 

x _{1},x _{2},x _{3},x _{4},x _{5}  x _{21},x _{22},…,x _{30}  ρ=0.55 
x _{6},x _{7},x _{8},x _{9},x _{10}  x _{31},x _{32},…,x _{40}  ρ=0.6 
x _{11},x _{12},x _{13},x _{14},x _{15}  x _{41},x _{42},…,x _{50}  ρ=0.65 
x _{16},x _{17},x _{18},x _{19},x _{20}  x _{51},x _{52},…,x _{60}  ρ=0.7 
In addition, we used standard lasso to select the variables in the first step, in alternative to adaptive lasso.
Sensitivity analysis
Average number and percentage of biologically relevant variables in the model with S N R=0.5 and (β _{ j }=0.1,j=1,2,…20)
Over 100 runs  Adaptive lasso  B1  B2  B3 

Average number of selected variables  41  41  41  41 
q=10 and ρ=0.1  
Average number of Biologically relevant variables  12  20  15  14 
Average percentage of Biologically relevant variables  29.3 %  48.8 %  36.6 %  34.1 % 
Standard deviation  9.1  0.86  1.24  3.11 
q=20and ρ=0.25  
Average number of Biologically relevant variables  12  38  34  29 
Average percentage of Biologically relevant variables  29.3 %  92.7 %  82.9 %  70.7 % 
Standard deviation  9.1  0.85  1.22  3.08 
q=30and ρ=0.3  
Average number of Biologically relevant variables  12  39  35  30 
Average percentage of Biologically relevant variables  29.3 %  95.1 %  85.4 %  73.2 % 
Standard deviation  9.1  0.85  1.23  3.09 
q=40and ρ=0.4  
Average number of Biologically relevant variables  12  39  36  31 
Average percentage of Biologically relevant variables  29.3 %  95.1 %  87.8 %  75.6 % 
Standard deviation  9.1  0.84  1.22  3.07 
Over 100 runs  Lasso  B1  B2  B3 
Average number of selected variables  53  53  53  53 
q=10 and ρ=0.1  
Average number of Biologically relevant variables  12  24  18  16 
Average percentage of Biologically relevant variables  22.6 %  45.3 %  34.0 %  30.2 % 
Standard deviation  10.2  0.99  1.55  3.94 
q=20and ρ=0.25  
Average number of Biologically relevant variables  12  46  39  34 
Average percentage of Biologically relevant variables (%)  22.6 %  86.8 %  72.1 %  64.2 % 
Standard deviation  10.2  0.97  1.53  3.89 
q=30and ρ=0.3  
Average number of Biologically relevant variables  12  47  39  36 
Average percentage of Biologically relevant variables (%)  22.6 %  88.7 %  73.6 %  67.9 % 
Standard deviation  10.2  0.97  1.53  3.89 
q=40and ρ=0.4  
Average number of Biologically relevant variables  12  48  40  37 
Average percentage of Biologically relevant variables (%)  22.6 %  90.6 %  75.5 %  69.8 % 
Standard deviation  10.2  0.96  1.51  3.86 
Simulation results
First we investigate to what extent our replacement method generates final models with more biologically relevant variables than using adaptive lasso or standard lasso alone.
Average number and percentage of biologically relevant variables in the model with S N R=0.5 and (β _{ j }=0.1,j=1,2,…20)
Over 100 runs  Adaptive lasso  B1  B2  B3 

Average number of selected variables  41  41  41  41 
Average number of Biologically relevant variables  12  38  34  29 
Average percentage of Biologically relevant variables (%)  29.3 %  92.7 %  82.9 %  70.7 % 
Standard deviation  9.1  0.85  1.22  3.08 
PMSE (absolute)  1.148  1.145  1.143  1.154 
PRPMSE %  100 %  99.7 %  99.6 %  100.5 % 
(St.dev)  (0.89)  (1.53)  (5.98)  
Favorable substitution %  91 %  78 %  69 %  
(St.dev)  (0.99)  (1.07)  (6.93)  
MISE  1.572  1.598  1.605  1.643 
Over 100 runs  Lasso  B1  B2  B3 
Average number of selected variables  53  53  53  53 
Average number of Biologically relevant variables  12  46  39  34 
Average percentage of Biologically relevant variables (%)  22.6 %  86.8 %  72.1 %  64.2 % 
Standard deviation  10.2  0.97  1.53  3.89 
PMSE (absolute)  1.576  1.570  1.567  1.596 
PRPMSE %  100 %  99.6 %  99.4 %  101.3 % 
(St.dev)  (0.97)  (1.81)  (6.71)  
Favorable substitution %  88 %  71 %  63 %  
(St.dev)  (1.02)  (1.52)  (7.68)  
MISE  1.876  1.914  1.927  1.941 
To compare the predictive performance of using different type of bags, we report in percentage the average (over 100 runs) ratio between PMSE of the substitute model and the adaptive lasso model(PRPMSE), using data \(\mathcal {D}_{3}\) for each type of bag, see Table 3. It shows that generating the model from bag types B1 and B2 performs slightly better than the adaptive lasso in terms of prediction performance — i.e. the predictive ability of the model is improved by incorporating the information on which genes are biologically relevant. But generating model from bag type B3 did not lead to improvement in terms of prediction.
To investigate this closer, we calculated the 95 % confidence interval for the PRPMSE, for each of the 100 simulation runs, by bootstrap. This gave 100 confidence intervals and we computed the proportion of those that contain 1 or less than 1, which would mean that the replacement does not significantly worsen the prediction power of the model. This percentage of favorable replacements is given in Table 3.
We compute the mean integrated squared error to compare the estimation accuracy of the approaches and report it in Table 3. It shows that the estimation accuracy is almost the same for all selection procedures, but our proposed bags give more biologically relevant variables than the adaptive lasso.
The results from the standard lasso is given in the bottom of Table 3. A larger number of variables are selected by adaptive lasso as expected. We get a lower percentage of biologically relevant variables compared to plain lasso. We also get a slightly lower percentage of favorable replacements from lasso than adaptive lasso. Predictive performance is worse for the lasso based models than for adaptive lasso. As before, compared with the lasso, for B1 and B2 there is an improvement in predictive performance; however, there is a deterioration in performance using bag type B3.
Other choices for the correlations than the one given in Table 1, are reported in Appendix A of the Additional file 1. They gave qualitatively similar results, see Table 2 in Appendix B in Additional file 1, where we used S N R=0.5 and (β _{ j }=0.1,j=1,2,…,20). Table 3 in Appendix B in Additional file 1 reports an experiment with S N R=0.5 and (β _{ j }=0.2,j=1,2,…,20). In Table 4 in Appendix B in Additional file 1 we used S N R=0.5 but (β _{ j }=0.8,j=1,2,…,20).
Average number and percentage of biologically relevant variables in the model with S N R=2 and (β _{ j }=0.1,j=1,2,…20)
Over 100 runs  Adaptive lasso  B1  B2  B3 

Average number of selected variables  44  44  44  44 
Average number of Biologically relevant variables  16  42  41  37 
Average percentage of Biologically relevant variables (%)  36.4 %  95.5 %  93.2 %  84.1 % 
Standard deviation  9.01  0.92  1.11  3.91 
PMSE (absolute)  1.895  1.878  1.880  1.901 
PRPMSE %  100 %  99.1 %  99.2 %  100.3 % 
(St.dev)  (1.01)  (2.14)  (6.16)  
Favorable substitution %  92 %  78 %  70 %  
(St.dev)  (0.99)  (1.37)  (8.92)  
MISE  1.986  2.003  2.052  2.097 
Over 100 runs  Lasso  B1  B2  B3 
Average number of selected variables  55  55  55  55 
Average number of Biologically relevant variables  16  48  45  40 
Average percentage of Biologically relevant variables (%)  22.8 %  87.3 %  81.8 %  72.7 % 
Standard deviation  10.2  0.99  1.53  4.12 
PMSE (absolute)  2.132  2.104  2.117  2.158 
PRPMSE %  100 %  98.7 %  99.3 %  101.2 % 
(St.dev)  (1.11)  (2.31)  (6.89)  
Favorable substitution %  89 %  70 %  68 %  
(St.dev)  (1.01)  (1.69)  (9.53)  
MISE  2.234  2.298  2.306  2.342 
Bone mineral density data
We applied our method to a gene expression data set previously studied in [14]. The data have been submitted to the European Bioinformatics Institute (EMBLEBI) ArrayExpress repository, ID: EMEXP1618. Rcode is given in Appendix C in Addtional file 1. For 84 women who had a transiliacal bone biopsy, gene expression measurements for 22815 gene probes were obtained. The data were normalized as described in [14] and we fit a linear regression model with L _{1} penalization with bone mineral density as response and preselected P=8649 covariates with the largest empirical variance.
Selected genes from adaptive lasso and each bag type (B1, B2, B3) based on biological reasons and PMSE and averaged PMSE over 100 bootstrap samples (BPMSE) in the test data
Adaptive lasso  Bag type B1  Bag type B2  Bag type B3  

AK3L1  ADAMTS2  ADAMTS2  RARA  
CSRNP3  RUNX2  RUNX2  CSRNP3  
FKBP14  SPTBN1  SPTBN1  VDR  
NF1  NF1  NF1  CSNK1G3  
PIAS4  ESR1  ESR1  PIAS4  
PLIN5  PLIN5  HGF  RHO  
PPIL2  BMP5  BMP5  SRGAP3  
RNF31  RNF31  RNF31  GLP1R G  
SRR  SMAD3  SRR  SRR  
TRPS1  SFRP1  SFRP1  TRPS1  
ZMAT3  ZMAT3  ZMAT3  ZMAT3  
PMSE  1.292  0.251  0.343  1.306 
BPMSE  1.074  0.242  0.298  1.286 
Selected genes from lasso and each bag type (B1, B2, B3) based on biological reasons and PMSE and averaged PMSE over 100 bootstrap samples (BPMSE) in the test data
Lasso  Bag type B1  Bag type B2  Bag type B3  

AK3L1  ADAMTS2  ADAMTS2  RARA  
CCHCR1  CCHCR1  CCHCR1  CCHCR1  
CRYGS  PPARA  PPARA  ESR1  
CSRNP3  RUNX2  RUNX2  CSRNP3  
FAF1  FAF1  FAF1  BMPR2  
FKBP14  SPTBN1  SPTBN1  VDR  
FLRT2  PDGFA  PDGFA  FLRT2  
KDM4A  SLC44A1  KDM4A7  KDM4A  
LOC642852  OSTM1  OSTM1  LOC642852  
MAPK8  BMP7  BMP7  WHAMML1 /// WHAMML2  
NF1  NF1  NF1  CSNK1G3  
PIAS4  ESR1  ESR1  PIAS4  
PLIN5  PLIN5  HGF  RHO  
PPIL2  BMP5  BMP5  SRGAP3  
RNF31  RNF31  RNF31  GLP1R G  
SRR  SMAD3  SRR  SRR  
TRPS1  SFRP1  SFRP1  TRPS1  
ZMAT3  ZMAT3  ZMAT3  ZMAT3  
PMSE  1.900  1.009  1.086  5.810 
BPMSE  1.871  1.001  1.024  5.053 
We can see from Tables 5 and 6, that the PMSE is smaller for the models based on bag types B1 and B2 compared with the initial adaptive lasso or lasso method. This demonstrates the merits of the proposed method: the model with more biologically relevant genes also leads to better out of sample predictions. On the other hand, the PMSE for bag type B3 is larger than for the other methods.
Discussion
We have presented a method that allows biological relevance of a large number of covariates to be elicited in a feasible manner, by fitting an initial model to generate a list of ‘interesting’ covariates. This list is produced by using an adaptive lasso model to generate a shortlist of variables, then extending this list to include a ‘bag’ of variables that are related to the original variables. Each gene in the union of these bags can then be classed, by a domain expert, as biologically interesting or not, and the adaptive lasso variables can be substituted for biologically interesting genes where possible. Simulations and a real data example demonstrate that our method leads to a model with more biological relevance, and better outofsample predictions compared with applying adaptive lasso alone, and we found similar results using standard lasso.
Based on our simulations, we recommend populating the ‘bags’ using genes highly correlated with the adaptive lasso genes, rather than considering the PMSE. We recommend a correlation threshold of 0.25 for constructing these bags; however, it is useful to conduct sensitivity analysis around this threshold to ensure that there is stability in selection of biologically relevant variables.
It is of interest to explore why bag types 1 and 2 (correlation based) perform better than bag type 3 (PMSE based). Our initial investigations show that this is because, with the PMSE bags, a small number of biologically relevant genes appear in many bags. This leads to a number of duplicate substitutions, and hence a sparser final model.
A strength of this approach is that it is more efficient to perform than a fully informative Bayesian approach, which would involve eliciting priors scaled to all genes. However, it takes longer than applying adaptive lasso or lasso with no incorporation of prior information. We believe the approach is a good tradeoff between modelling effort, domain expert input, and quality of the final model. The involvement of domain experts in the modelling process is also a strength because they may perceive the resulting model as being more relevant as they have invested in its production. A weakness is that the ‘pre screening’ stage could eliminate genes that the domain experts have a very strong prior belief of involvement in the relevant mechanistic processes. This could be alleviated by allowing a small number of prior known genes to appear in the substitution bags regardless of meeting the correlation or PMSE criteria. For clarity, we explained the method using linear models, but the extension to generalised linear models and multilevel models is clear. One possible criticism of the approach is that the preference for using ‘known’ genes in the final models may prevent discovery of novel mechanisms. If there is a very strong signal for an unknown gene being a prognosticator, this would survive the postprocessing to appear in the final model.
This work could be extended by incorporating richer biological information about the genes — we used a binary classification of ‘interesting’ and ‘not interesting’ — this could be extended to a continuous importance measure of each gene. The challenge then would be how to weight the biological information appropriately against the predictive ability.
Conclusion
Our method allows feasible incorporation of biological knowledge into predictive models with a large number of potential covariates, leading to models with greater face validity, generalisability and interpretability, without adversely affecting predictive performance.
Declarations
Acknowledgments
MS was supported by the Medical Research Council (MRC) Grant MR/K006665/1. We thank Ingrid K. Glad and Marissa LeBlanc for useful discussions on the bag idea.
Funding
Medical Research Council Award Number: MR/K006665/1  Recipient Matthew Sperrin
Availability of data and materials
The data have been submitted to the European Bioinformatics Institute (EMBLEBI) ArrayExpress repository, ID: EMEXP1618.
Authors’ contributions
AF and TK conceived the method. AF, TK, TJ and MS designed the experiments. TK implemented the methods, run all analysis and prepared results. SR provided gene expression data from bone biopsies and molecular expertise on the study. All authors discussed methods and results and contributed to writing of the paper. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Not applicable.
Ethics approval and consent to participate
Ethical approval was not required as the data used in this study are publicly available.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Authors’ Affiliations
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